Branched 3-phenylpropionic acid derivatives and their use

ABSTRACT

The present application relates to novel 3-phenylpropionic acid derivatives which carry a branched or cyclic alkyl substituent in the 3-position, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular diseases.

This application is a divisional application of U.S. application Ser.No. 14/304,171, filed Jun. 13, 2014, the contents of which areincorporated herein by reference for all purposes, which is acontinuation of U.S. application Ser. No. 13/431,934, now U.S. Pat. No.8,796,335, filed Mar. 27, 2012, which claims priority to GermanApplication No. 102011007272.1 filed Apr. 13, 2011.

The present application relates to novel 3-phenylpropionic acidderivatives which carry a branched or cyclic alkyl substituent in the3-position, to processes for their preparation, to their use for thetreatment and/or prevention of diseases and to their use for preparingmedicaments for the treatment and/or prevention of diseases, inparticular for the treatment and/or prevention of cardiovasculardiseases.

One of the most important cellular transmission systems in mammaliancells is cyclic guanosine monophosphate (cGMP). Together with nitricoxide (NO), which is released from the endothelium and transmitshormonal and mechanical signals, it forms the NO/cGMP system. Guanylatecyclases catalyse the biosynthesis of cGMP from guanosine triphosphate(GTP). The representatives of this family disclosed to date can bedivided both according to structural features and according to the typeof ligands into two groups: the particulate guanylate cyclases which canbe stimulated by natriuretic peptides, and the soluble guanylatecyclases which can be stimulated by NO. The soluble guanylate cyclasesconsist of two subunits and very probably contain one haem perheterodimer, which is part of the regulatory site. The latter is ofcentral importance for the mechanism of activation. NO is able to bindto the iron atom of haem and thus markedly increase the activity of theenzyme. Haem-free preparations cannot, by contrast, be stimulated by NO.Carbon monoxide (CO) is also able to attach to the central iron atom ofhaem, but the stimulation by CO is distinctly less than that by NO.

Through the production of cGMP and the regulation, resulting therefrom,of phosphodiesterases, ion channels and protein kinases, guanylatecyclase plays a crucial part in various physiological processes, inparticular in the relaxation and proliferation of smooth muscle cells,in platelet aggregation and adhesion and in neuronal signaltransmission, and in disorders caused by an impairment of theaforementioned processes. Under pathophysiological conditions, theNO/cGMP system may be suppressed, which may lead for example to highblood pressure, platelet activation, increased cellular proliferation,endothelial dysfunction, atherosclerosis, angina pectoris, heartfailure, thromboses, stroke and myocardial infarction.

A possible way of treating such disorders which is independent of NO andaims at influencing the cGMP signaling pathway in organisms is apromising approach because of the high efficiency and few side effectswhich are to be expected.

Compounds, such as organic nitrates, whose effect is based on NO have todate been exclusively used for the therapeutic stimulation of solubleguanylate cyclase. NO is produced by bioconversion and activates solubleguanylate cyclase by attaching to the central iron atom of haem. Besidesthe side effects, the development of tolerance is one of the crucialdisadvantages of this mode of treatment [O. V. Evgenov et al., NatureRev. Drug Disc. 5 (2006), 755].

Substances which directly stimulate soluble guanylate cyclase, i.e.without previous release of NO, have been identified in recent years.The indazole derivative YC-1 was the first NO-independent buthaem-dependent sGC stimulator described [Evgenov et at, ibid.]. Based onYC-1, further substances were discovered which are more potent than YC-1and show no relevant inhibition of phosphodiesterases (PDE). This led tothe identification of the pyrazolopyridine derivatives BAY 41-2272, BAY41-8543 and BAY 63-2521. Together with the recently publishedstructurally different substances CMF-1571 and A-350619, these compoundsform the new class of the sGC stimulators [Evgenov et al., ibid.]. Acommon characteristic of this substance class is an NO-independent andselective activation of the haem-containing sGC. In addition, the sGCstimulators in combination with NO have a synergistic effect on sGCactivation based on a stabilization of the nitrosyl-haem complex. Theexact binding site of the sGC stimulators at the sGC is still beingdebated. If the haem group is removed from the soluble guanylatecyclase, the enzyme still has a detectable catalytic basal activity,i.e. cGMP is still being formed. The remaining catalytic basal activityof the haem-free enzyme cannot be stimulated by any of the stimulatorsmentioned above [Evgenov et al., ibid.].

In addition, NO- and haem-independent sGC activators, with BAY 58-2667as prototype of this class, have been identified. Common characteristicsof these substances are that in combination with NO they only have anadditive effect on enzyme activation, and that the activation of theoxidized or haem-free enzyme is markedly higher than that of thehaem-containing enzyme [Evgenov at al., ibid.; J. P. Stasch at al., Br.J. Pharmacol. 136 (2002), 773; J. P. Stasch et al., J. Clin. Invest. 116(2006). 2552]. Spectroscopic studies show that BAY 58-2667 displaces theoxidized haem group which, as a result of the weakening of theiron-histidine bond, is attached only weakly to the sGC. It has alsobeen shown that the characteristic sGC haem binding motifTyr-x-Ser-x-Arg is absolutely essential both for the interaction of thenegatively charged proprionic acids of the haem group and for the actionof BAY 58-2667. Against this background, it is assumed that the bindingsite of BAY 58-2667 at the sGC is identical to the binding site of thehaem group [J. P. Stasch et al., J. Clin. Invest. 116 (2006), 2552].

The compounds described in the present invention are now likewisecapable of activating the haem-free form of soluble guanylate cyclase.This is also confirmed by the fact that these novel activators firstlyhave no synergistic action with NO at the haem-containing enzyme andthat secondly their action cannot be blocked by the haem-dependentinhibitor of soluble guanylate cyclase,1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), but is evenpotentiated by this inhibitor [cf. O. V. Evgenov et al., Nature Rev.Drug Disc. 5 (2006), 755; J. P. Stasch et al., J. Clin. Invest. 116(2006), 2552].

It was thus an object of the present invention to provide novelcompounds which act as activators of soluble guanylate cyclase in themanner described above and can be used as such in particular for thetreatment and prevention of cardiovascular disorders.

WO00/64888-A1, EP 1 216 980-A1, EP 1 285 908-A1, EP 1 348 698-A1, EP 1375 472-A1, EP 1 452 521-A1, US 2005/0187266-A1 and US 2005/0234066-A1describe various arylalkanecarboxylic acid derivatives as PPAR agonistsfor treating diabetes, dyslipidaemnia, arteriosclerosis, obesity andother disorders. EP 1 312 601-A1 and EP 1431267-A1 disclose substitutedarylalkanecarboxylic acids as PGE₂ receptor antagonists for thetreatment, for example, of states of pain, urological disorders,Alzheimer's disease and cancer. Furthermore, WO 2005/086661-A2 claimsarylalkanecarboxylic acids as GPR40 modulators for the treatment ofdiabetes and dyslipidaemias, and WO2004/099170-A2, WO 2006/050097-A1 andWO 2006/055625-A2 describe phenyl-substituted carboxylic acids as PTP-1Binhibitors for the treatment of diabetes, cancer and neurodegenerativedisorders. Furthermore, individual phenylacetamido-substitutedphenylalkanecarboxylic acids which, in the form of non-covalent mixturesimprove the delivery of active peptide compounds within the body areknown from WO 96/12473-A1 and WO 9630036-A1. WO 2009/067493-A2 claims3,5-disubstituted phenylacetic acid derivatives for the treatment ofAlzheimer's disease. WO 2009/127338-A1 and WO 2010/102717-A1 discloseoxoheterocyclically substituted carboxylic acid derivatives which act asactivators of soluble guanylate cyclase.

The present invention provides compounds of the general formula (I)

-   in which-   R¹, R² and R³ independently of one another represent hydrogen or    methyl,-   L represents a bond or represents —CH₂—.-   R^(4A) and R^(4B) independently of one another represent methyl,    trifluoromethyl or ethyl-   or-   R^(4A) and R^(4B) are attached to one another and together with the    carbon atom to which they are attached form a cyclopropyl or    cyclobutyl ring which may be substituted up to two times by    fluorine,-   R⁵ represents hydrogen, fluorine, methyl or methoxy,-   R⁶ represents hydrogen, fluorine, chlorine, bromine, cyano, methyl,    trifluoromethyl, ethyl, methoxy or trifluoromethoxy,-   R⁷ represents hydrogen, fluorine, chlorine or methyl,-   R^(8A) represents methyl or ethyl,-   R^(8B) represents trifluoromethyl,-   or-   R^(8A) and R^(8B) are attached to one another and together with the    carbon atom to which they are attached form an optionally    difluoro-substituted cyclopentyl ring of the formula

-   R⁹ represents fluorine, chlorine, bromine, cyano, (C₁-C₄)-alkyl,    (C₂-C₄)-alkenyl, cyclopropyl or cyclobutyl, where    -   (C₁-C₄)-alkyl and (C₂-C₄)-alkenyl may be substituted up to three        times by fluorine and    -   cyclopropyl and cyclobutyl may be substituted up to two times by        fluorine,-   and-   R¹⁰ represents hydrogen, fluorine, chlorine, methyl, trifluoromethyl    ethyl or methoxy,    and salts, solvates and solvates of the salts thereof.

Compounds according to the invention are the compounds of the formula(I) and their salts, solvates and solvates of the salts, the compoundsincluded in the formula (I) of the formulae mentioned in the followingand their salts, solvates and solvates of the salts, and the compoundsincluded in the formula (I) and mentioned in the following as embodimentexamples and their salts, solvates and solvates of the salts, where thecompounds included in the formula (I) and mentioned in the following arenot already salts, solvates and solvates of the salts.

Preferred salts in the context of the present invention arephysiologically acceptable salts of the compounds according to theinvention. Salts which are not themselves suitable for pharmaceuticaluses but can be used, for example, for isolation, purification orstorage of the compounds according to the invention are also included.

Physiologically acceptable salts of the compounds according to theinvention include in particular salts of conventional bases, such as, byway of example and preferably, alkali metal salts (e.g. sodium andpotassium salts), alkaline earth metal salts (e.g. calcium and magnesiumsalts) and ammonium salts derived from ammonia or organic amines having1 to 16 C atoms, such as, by way of example and preferably, ethylamine,diethylamine, triethylamine, N,N-diisopropylethylamine,monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanoldiethylaminoethanol, procaine, dicyclohexylamine, dibenzylamine,N-methylpiperidine, N-methylmorpholine, arginine, lysine and1,2-ethylenediamine.

Solvates in the context of the invention are designated as those formsof the compounds according to the invention which form a complex in thesolid or liquid state by coordination with solvent molecules. Hydratesare a specific form of solvates, in which the coordination takes placewith water. Hydrates are preferred solvates in the context of thepresent invention.

Depending on their structure, the compounds according to the inventionmay exist in different stereoisomeric forms. i.e. in the form ofconfigurational isomers or if appropriate also as conformational isomers(enantiomers and/or diastereomers, including those in the case ofatropisomers). The present invention therefore encompasses theenantiomers or diastereomers and the respective mixtures thereof. Thestereoisomerically uniform constituents can be isolated from suchmixtures of enantiomers and/or diastereomers in a known manner;chromatography processes are preferably used for this, in particularHPLC chromatography on an achiral or chiral phase.

Where the compounds according to the invention can occur in tautomericforms, the present invention encompasses all the tautomeric forms.

The present invention also encompasses all suitable isotopic variants ofthe compounds according to the invention. An isotopic variant of acompound according to the invention is understood here to mean acompound in which at least one atom within the compound according to theinvention has been exchanged for another atom of the same atomic umber,but with a different atomic mass than the atomic mass which usually orpredominantly occurs in nature. Examples of isotopes which can beincorporated into a compound according to the invention are those ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine,chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹³C,¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I,¹²⁴I, ¹²⁹I and ¹³¹I. Particular isotopic variants of a compoundaccording to the invention, especially those in which one or moreradioactive isotopes have been incorporated, may be beneficial, forexample, for the examination of the mechanism of action or of the activecompound distribution in the body; due to comparatively easypreparability and detectability, especially compounds labelled with ³Hor ¹⁴C isotopes are suitable for this purpose. In addition, theincorporation of isotopes, for example of deuterium, can lead toparticular therapeutic benefits as a consequence of greater metabolicstability of the compound, for example an extension of the half-life inthe body or a reduction in the active dose required; such modificationsof the compounds according to the invention may therefore in some casesalso constitute a preferred embodiment of the present invention.Isotopic variants of the compounds according to the invention can beprepared by generally used processes known to those skilled in the art,for example by the methods described below and the methods described inthe working examples, by using corresponding isotopic modifications ofthe particular reagents and/or starting compounds therein.

The present invention moreover also includes prodrugs of the compoundsaccording to the invention. The term “prodrugs” here designatescompounds which themselves can be biologically active or inactive, butare converted (for example metabolically or hydrolytically) intocompounds according to the invention during their dwell time in thebody.

As prodrugs, the present invention comprises in particular hydrolysableester derivatives of the carboxylic acids of the formula (I) accordingto the invention. These are to be understood as meaning esters which canbe hydrolysed to the free carboxylic acids, as the compounds that aremainly active biologically, in physiological media, under the conditionsof the biological tests described later and in particular in vivo byenzymatic or chemical routes. (C₁-C₄)-alkyl esters, in which the alkylgroup can be straight-chain or branched, are preferred as such esters.Particular preference is given to methyl, ethyl or tert-butyl esters.

In the context of the present invention, the substituents have thefollowing meaning, unless specified otherwise:

(C₁-C₄)-Alkyl in the context of the invention represents astraight-chain or branched alkyl radical having 1 to 4 carbon atoms. Thefollowing may be mentioned by way of example and by way of preference:methyl, ethyl, n-propyl isopropyl, n-butyl, isobutyl, sec-butyl andtert-butyl.

(C₂-C₄)-Alkenyl and (C₂-C₃)-alkenyl in the context of the inventionrepresent a straight-chain or branched alkenyl radical having a doublebond and 2 to 4 and 2 or 3 carbon atoms, respectively. A straight-chainor branched alkenyl radical having 2 or 3 carbon atoms is preferred. Thefollowing may be mentioned by way of example and by way of preference:vinyl, allyl, n-prop-1-en-1-yl, iso-propenyl, n-but-1-en-1-yl,n-but-2-en-1-yl, n-but-3-en-1-yl, 2-methylprop-1-en-1-yl and2-methylprop-2-en-1-yl.

In the context of the present invention, all radicals which occur morethan once are defined independently of one another. If radicals in thecompounds according to the invention are substituted, the radicals maybe mono- or polysubstituted, unless specified otherwise. Substitution byone, two or three identical or different substituents is preferred.Particular preference is given to substitution by one or two identicalor different substituents.

In the context of the present invention, preference is given tocompounds of the formula (I) in which

-   R¹ represents hydrogen or methyl,-   R² represents hydrogen,-   R³ represents hydrogen or methyl,-   L represents a bond or represents —CH₂—.-   R^(4A) and R^(4B) both represent methyl or are attached to one    another and together with the carbon atom to which they are attached    form a cyclopropyl or cyclobutyl ring which may be substituted up to    two times by fluorine,-   R⁵ represents hydrogen, fluorine, methyl or methoxy,-   R⁶ represents fluorine, chlorine, methyl or ethyl,-   R⁷ represents hydrogen or fluorine.-   R^(8A) represents methyl,-   R^(8B) represents trifluoromethyl,-   or-   R^(8A) and R^(8B) are attached to one another and together with the    carbon atom to which they are attached form a difluoro-substituted    cyclopentyl ring of the formula

-   R⁹ represents fluorine, chlorine, (C₁-C₄)-alkyl, (C₂-C₃)-alkenyl,    cyclopropyl or cyclobutyl, where    -   (C₁-C₄)-alkyl and (C₂-C₃)-alkenyl may be substituted up to three        times by fluorine    -   and    -   cyclopropyl and cyclobutyl may be substituted up to two times by        fluorine,-   and-   R¹⁰ represents hydrogen, fluorine, chlorine, methyl or methoxy,-   and salts, solvates and solvates of the salts thereof.

A particular embodiment of the present invention comprises compounds ofthe formula (I) in which

-   R¹ and R² both represent hydrogen,-   and salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention comprisescompounds of the formula (I) in which

-   R³ represents hydrogen or methyl-   and-   L represents a bond,-   and salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention comprisescompounds of the formula (I) in which

-   R³ represents hydrogen-   and-   L represents —CH₂—,-   and salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention comprisescompounds of the formula (I) in which

-   R^(4A) and R^(4B) both represent methyl-   and-   R⁵ represents hydrogen,-   and salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention comprisescompounds of the formula (I) in which

-   R^(4A) and R^(4B) are attached to one another and together with the    carbon to which they are attached form a cyclopropyl or cyclobutyl    ring which may be substituted up to two times by fluorine,-   and-   R⁵ represents hydrogen, fluorine or methyl,-   and salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention comprisescompounds of the formula (I) in which

-   R⁶ represents chlorine-   and-   R⁷ represents hydrogen,-   and salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention comprisescompounds of the formula (I) in which

-   R^(8A) represents methyl-   and-   R^(8B) represents trifluoromethyl,-   and salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention comprisescompounds of the formula (I) in which

-   R^(8A) and R^(8B) are attached to one another and together with the    carbon atom to which they are attached form a difluoro-substituted    cyclopentyl ring of the formula

-   and salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention comprisescompounds of the formula (I) in which

-   R⁹ represents fluorine, chlorine, (C₁-C₄)-alkyl or cyclopropyl,    where (C₁-C₄)-alkyl may be substituted up to three times by fluorine    and cyclopropyl may be substituted up to two times by fluorine,-   and salts, solvates and solvates of the salts thereof.

A further particular embodiment of the present invention comprisescompounds of the formula (I) in which

-   R¹⁰ represents hydrogen, fluorine, chlorine, methyl or methoxy,-   and salts, solvates and solvates of the salts thereof.

Particular preference in the context of the present invention is givento compounds of the formula (I) in which

-   R¹ and R² both represent hydrogen,-   R³ represents hydrogen or methyl,-   L represents a bond or represents —CH₂—,-   R^(4A) and R^(4B) both represent methyl or are attached to one    another and together with the carbon atom to which they are attached    form a cyclopropyl or cyclobutyl ring which may be substituted up to    two times by fluorine,-   R⁵ represents hydrogen, fluorine or methyl,-   R⁶ represents chlorine,-   R⁷ represents hydrogen,-   R^(8A) represents methyl,-   R^(8B) represents trifluoromethyl,-   R⁹ represents fluorine, chlorine, methyl, trifluromethyl, ethyl,    2,2,2-trifluoroethyl, isopropyl, tert-butyl, cyclopropyl or    2,2-difluorocyclopropyl,-   and-   R¹⁰ represents hydrogen fluorine, methyl or methoxy,-   and salts, solvates and solvates of the salts thereof.

Of particular importance in the context of the present invention arecompounds of the formula (I-A)

in which the carbon atom marked * of the phenylacetamide grouping hasthe S-configuration shownandthe radicals R³, R^(4A), R^(4B), R⁵, R⁶, R^(8A), R^(8B), R⁹ and R¹⁰ andL each have the meanings given above,and salts, solvates and solvates of the salts thereof.

The definitions of radicals indicated specifically in the respectivecombinations or preferred combinations of radicals are replaced asdesired irrespective of the particular combinations indicated for theradicals also by definitions of radicals of other combinations.Combinations of two or more of the abovementioned preferred ranges arevery particularly preferred.

The invention furthermore provides a process for preparing the compoundsof the formula (I) according to the invention, characterized in that acarboxylic acid of the formula (II)

in which R^(8A), R^(8B), R⁹ and R¹⁰ have the meanings given above,is coupled in an inert solvent with the aid of a condensing agent or viathe intermediate of the corresponding carbonyl chloride in the presenceof a base with an amine of the formula (III)

in which L, R¹, R², R³, R^(4A), R^(4B), R⁵, R⁶ and R⁷ have the meaningsgiven aboveandT¹ represents (C₁-C₄)-alkyl or benzyl,to give a carboxamide of the formula (IV)

in which L, R¹, R², R³, R^(4A), R^(4B), R⁵, R⁶, R⁷, R^(8A), R^(8B), R⁹,R¹⁰ and T¹ have the meanings given above,and the ester radical T¹ is then removed by basic or acidic solvolysisor, in the case that T¹ represents benzyl, also by hydrogenolysis togive the carboxylic acid of the formula (I)and the compounds of the formula (I) are optionally separated by methodsknown to the person skilled in the art into their enantiomers and/ordiastereomers and/or reacted with the appropriate (i) solvents and/or(ii) bases to give their solvates salts and/or solvates of the salts.

Inert solvents for the process step (II)+(III)→(IV) [amide coupling]are, for example, ethers such as diethyl ether, ten-butyl methyl ether,tetrahydrofuran, 1,4-dioxan, glycol dimethyl ether or diethylene glycoldimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane,cyclohexane or mineral oil fractions, halogenated hydrocarbons such asdichloromethane, trichloromethane, carbon tetrachloride,1,2-dichloroethane, trichloroethylene or chlorobenzene, or othersolvents such as acetone, acetonitrile, ethyl acetate, pyridine,dimethyl sulphoxide (DMSO), N,N-dimethylformamide (DMF),N,N′-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP). It isalso possible to use mixtures of the solvents mentioned. Preference isgiven to using dichloromethane, tetrahydrofuran, dimethylformamide ormixtures of these solvents.

Suitable condensing agents for these coupling reactions are, forexample, carbodiimides such as N,N′-diethyl-, N,N′-dipropyl-,N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide (DCC) orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),phosgene derivatives such as N,N′-carbonyldiimidazole (CDI) or isobutylchloroformate, 1,2-oxazolium compounds such as2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl5-methylisoxazolium perchlorate, acyl-amino compounds such as2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, α-chloroenamines such as1-chloro-2-methyl-1-dimethylamino-1-propene, phosphorus compounds suchas propane-phosphonic anhydride, diethyl cyanophosphonate,bis(2-oxo-3-oxazolidinyl)phosphoryl chloride,benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateor benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), or uronium compounds such asO-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate(TBTU), O-(benzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (HBTU),2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TPTU), O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (HATU) orO-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TCTU), if appropriate in combination with furtherauxiliaries such as 1-hydroxybenzotriazole (HOBt) orN-hydroxysuccinimide (HOSu), and as bases alkali metal carbonates, forexample sodium carbonate or potassium carbonate, or tertiary amine basessuch as triethylamine, N-methylmorpholine, N-methylpiperidine,N,N-diisopropylethylamine, pyridine or 4-N,N-dimethylaminopyridine.Preference is given to usingO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) in combination with pyridine orN,N-diisopropylethylamine, orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) incombination with 1-hydroxybenzotriazole (HOBt) and triethylamine, or1-chloro-2-methyl-1-dimethylamino-1-propene together with pyridine.

The reaction (II)+(III)→(IV) is generally carried out in a temperaturerange of from 0° C. to +60° C., preferably at from +10° C. to +40° C.

When a carbonyl chloride corresponding to the compound (II) is used, thecoupling with the amine component (III) is carried out in the presenceof a customary organic auxiliary base such as triethylamine,N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine,pyridine, 4-N,N-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-en(DBU) or 1,5-diazabicyclo-[4.3.0]non-5-ene (DBN). Preference is given tousing triethylamine or N,N-diisopropylethylamine.

The reaction of the amine (III) with the carbonyl chloride is generallycarried out in a temperature range of from −20° C. to +60° C. preferablyin the range from −10° C. to +30° C.

For their part, the preparation of the carbonyl chlorides is carried outin a customary manner by treating the carboxylic acid (II) with thionylchloride or oxalyl chloride.

The removal of the ester group T¹ in process step (IV)→(I) is carriedout by customary methods by treating the ester in inert solvents withacids or bases, where in the latter variant the salt initially formed isconverted by treatment with acid into the free carboxylic acid. In thecase of the tert-butyl esters, the ester cleavage is preferably carriedout using acids. Benzyl esters are preferably cleaved by hydrogenolysis(hydrogenation) in the presence of a suitable catalyst such as, forexample, palladium on activated carbon.

Suitable inert solvents for these reactions are water or organicsolvents customary for ester cleavage. These preferably include alcoholssuch as methanol, ethanol, n-propanol, isopropanol, n-butanol ortert-butanol, or ethers such as diethyl ether, tetrahydrofuran, dioxaneor glycol dimethyl ether, or other solvents such as acetone,dichloromethane, dimethylformamide or dimethyl sulphoxide. It is alsopossible to use mixtures of the solvents mentioned above. In the case ofa basic ester hydrolysis, preference is given to using mixtures of waterwith dioxane, tetrahydrofuran, methanol and/or ethanol. In the case ofthe reaction with trifluoroacetic acid, preference is given to usingdichloromethane and in the case of the reaction with hydrogen chloride,preference is given to using tetrahydrofuran, diethyl ether, dioxane orwater.

Suitable bases are the customary inorganic bases. These include inparticular alkali or alkaline earth metal hydroxides such as, forexample, lithium hydroxide, sodium hydroxide, potassium hydroxide orbarium hydroxide, or alkali or alkaline earth metal carbonates such assodium carbonate, potassium carbonate or calcium carbonate. Preferenceis given to lithium hydroxide, sodium hydroxide or potassium hydroxide.

Suitable acids for the ester cleavage are, in general, sulphuric acid,hydrogen chloride/hydrochloric acid, hydrogen bromide/hydrobromic acid,phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulphonicacid, methanesulphonic acid or trifluoromethanesulphonic acid ormixtures thereof, if appropriate with addition of water. Preference isgiven to hydrogen chloride or trifluoroacetic acid in the case of thetert-butyl esters and hydrochloric acid in the case of the methylesters.

The ester cleavage is generally carried out in a temperature range offrom −20° C. to +100° C., preferably at from 0° C. to +60° C.

The intermediates of the formula (II) can be prepared, for example, by

[A] initially deprotonating a carboxylic acid of the formula (V)

-   -   in which R^(8A) and R^(8B) have the meanings given above    -   and    -   T² represents (C₁-C₄)-alkyl or benzyl,    -   in an inert solvent with the aid of a base and then arylating in        the presence of a suitable palladium catalyst with a phenyl        bromide of the formula (VI)

-   -   in which R⁹ and R¹⁰ have the meanings give above,    -   to give a compound of the formula (VII)

-   -   in which R^(8A), R^(8B), R⁹, R¹⁰ and T² have the meanings given        above,        or        [B] alkylating a phenylacetic ester of the formula (VIII)

-   -   in which R⁹ and R¹⁰ have the meanings given above    -   and    -   T² represents (C₁-C₄)-alkyl or benzyl,    -   in an inert solvent in the presence of a base with a compound of        the formula (IX)

-   -   in which R^(8A) and R^(8B) have the meanings given above    -   and    -   X¹ represents a suitable leaving group such as, for example,        bromine or iodine,    -   to give the compound of the formula (VII)

-   -   in which R^(8A), R^(8B), R⁹, R¹⁰ and T² have the meanings given        above,        and then in each case removing the ester radical T² by basic or        acidic solvolysis or, in the case that T² represents benzyl,        also by hydrogenolysis, giving the carboxylic acid (II).

The arylation reaction in process step (V)+(VI)→(VII) is preferablycarried out in toluene or toluene/tetrahydrofuran mixtures in atemperature range of from +20° C. to +100° C. Here, the base used fordeprotonating the ester (V) is preferably lithiumbis(trimethylsilyl)amide. Suitable palladium catalysts are, for example,palladium(I) acetate or tris(dibenzylideneacetone)dipalladium, in eachcase in combination with an electron-rich, sterically demandingphosphine ligand such as2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl or2-di-tert-butyl-phosphino-2′-(N,N-dimethylamino)biphenyl [cf., forexample, W. A. Moradi, S. L. Buchwald, J. Am. Chem. Soc. 123, 7996-8002(2001)].

Inert solvents for the alkylation reaction (VII)+(IX)→(VII) are, forexample ethers such as diethyl ether, methyl tert-butyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethylether, hydrocarbons such as benzene, toluene, xylene, hexane,cyclohexane or mineral oil fractions, or dipolar aprotic solvents suchas N,N-dimethylformamide (DMF), dimethyl sulphoxide (DMSO),N,N′-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP). It isalso possible to use mixtures of the solvents mentioned. Preference isgiven to using tetrahydrofuran, dimethylformamide or mixtures thereof.

Suitable bases for the process step (VIII)+(IX)→(VII) are customarystrong inorganic or organic bases. These include in particular alkalimetal alkoxides such as sodium methoxide or potassium methoxide, sodiumethoxide or potassium ethoxide or sodium tert-butoxide or potassiumtert-butoxide, alkali metal hydrides such as sodium hydride or potassiumhydride, or amides such as lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide or potassium bis(trimethylsilyl)-amide orlithium diisopropylamide. Preference is given to using potassiumtert-butoxide, sodium hydride or lithium diisopropylamide.

The reaction (VIII)+(IX)→(VII) is generally carried out in a temperaturerange of from −80° C. to +40° C., preferably at from −20° C. to +20° C.

The removal of the ester group T² in process step (VII)→(II) is carriedout in an analogous manner as described above for the ester radical T¹.

Alternatively, intermediates of the formula (II-A)

in which R⁹ and R¹⁰ have the meanings given above,can also be prepared by initially converting the phenylacetic ester ofthe formula (VIII)

in which R⁹, R¹⁰ and T³ have the meanings given above,by base-induced addition to 2-cyclopenten-1-one into a compound of theformula (X)

in which R⁹, R¹⁰ and T² have the meanings given above,then fluorinating this compound with1,1′-[(trifluoro-λ⁴-sulphanyl)imino]bis(2-methoxyethane) under borontrifluoride catalysis to give a compound of the formula (VII-A)

in which R⁹, R¹⁰ and T² have the meanings given above,and subsequently removing the ester group T² again giving the carboxylicacid (II-A).

In process step (VII)→(X), for deprotonating the ester (VIII),preference is given to using an amide base such as lithiumdiisopropylamide or lithium bis(trimethylsilyl)amide. For thedeoxy-fluorination in the transformation (X)→(VII-A), instead of the1,1′-[(trifluoro-λ⁴-sulphanyl)-imino]bis(2-methoxyethane)(“Desexofluor”) mentioned above, it is also possible, if appropriate, toemploy other known fluorinating agents, such as diethylaminosulphurtrifluoride (DAST) or morpholinosulphur trifluoride (morpho-DAST) [forthe reaction sequence (VIII)→(X)→(VII-A), cf., for example, T. Mase etal., J. Org. Chem. 66 (20), 6775-6786 (2001)].

Depending on their substitution pattern, the inter mediates of theformula (Ml) can be prepared, for example, by either

[C-1] reacting a phosphonoacetic ester of the formula (XI)

-   -   in which R¹ and T¹ have the meanings given above    -   and    -   R¹¹ represents (C₁-C₄)-alkyl,    -   in an inert solvent in a base-induced olefination reaction with        a 3-nitrobenzoyl compound of the formula (XII)

-   -   in which L, R^(4A), R^(4B), R⁵, R⁶ and R⁷ have the meanings        given above,    -   to give a compound of the formula (XIII)

-   -   in which L, R¹, R^(4A), R^(4B), R⁵, R⁶, R⁷ and T¹ have the        meanings given above,    -   and then hydrogenating this compound in the presence of a        suitable palladium or platinum catalyst to give a        3-(3-aminophenyl)propionic ester of the formula (III-A)

-   -   in which L, R¹, R^(4A), R^(4B), R⁵, R⁶, R⁷ and T¹ have the        meanings given above,        or        [C-2] reacting a phosphonoacetic ester of the formula (XI)

-   -   in which R¹ and T¹ have the meanings given above    -   and    -   R¹¹ represents (C₁-C₄)-alkyl    -   in an inert solvent in a base-induced olefination reaction with        a protected 3-aminobenzoyl compound of the formula (XIV)

-   -   in which L, R^(4A), R^(4B), R⁵, R⁶ and R⁷ have the meanings        given above    -   and    -   PG represents benzyl or 4-methoxybenzyl as inert amino        protective group    -   to give a compound of the formula (XV)

-   -   in which L, PG, R¹, R^(4A), R^(4B), R⁵, R⁶, R⁷ and T¹ have the        meanings given above,    -   then either (i) reducing this compound with magnesium in        methanol to give a compound of the formula (XVI)

-   -   in which L, PG, R¹, R^(4A), R^(4B), R⁵, R⁶, R⁷ and T¹ have the        meanings given above,    -   and subsequently removing the amino protective groups PG        according to customary methods by hydrogenolysis or oxidatively        giving the 3-(3-aminophenyl)propionic ester of the formula        (III-A)

-   -   in which L, R¹, R^(4A), R^(4B), R⁵, R⁶, R⁷ and T¹ have the        meanings given above,    -   or (ii) converting the compound of the formula (XV) in a        one-step process by hydrogenation in the presence of a suitable        palladium or platinum catalyst into the        3-(3-aminophenyl)propionic ester of the formula (III-A),        or        [D] coupling an acrylic ester derivative of the formula (XVII)

-   -   in which L, R¹, R^(4A), R^(4B), R⁵ and T¹ have the meanings        given above,    -   in an inert solvent under palladium catalysis with a 3-amino- or        3-nitrophenyl bromide of the formula (XVIII)

-   -   in which R⁶ and R⁷ have the meanings given above    -   and    -   R¹² represents amino or nitro,    -   to give a compound of the formula (XIX)

-   -   in which L, R¹, R^(4A), R^(4B), R⁵, R⁶, R⁷, R¹² and T¹ have the        meanings given above,    -   and then reducing this compound with hydrogen in the presence of        a suitable palladium or platinum catalyst or, in the case that        R¹² represents amino, alternatively with magnesium in methanol        to give the 3-(3-aminophenyl)propionic ester of the formula        (III-A)

-   -   in which L, R¹, R^(4A), R^(4B), R⁵, R⁶, R⁷ and T¹ have the        meanings given above.        or        [E-1] converting a phenyl iodide of the formula (XX)

-   -   in which R⁶ and R⁷ have the meanings given above,    -   in an inert solvent with isopropylmagnesium chloride in the        presence of lithium chloride into the corresponding        phenylmagnesium compound, then coupling this compound in situ        under copper(I) catalysis with an alkylidenemalonic ester of the        formula (XXI)

-   -   in which L, R³, R^(4A), R^(4B) and R⁵ have the meanings given        above    -   and    -   T³ represents methyl or ethyl,    -   to give a compound of the formula (XXII)

-   -   in which L, R³, R^(4A), R^(4B), R⁵, R⁶, R⁷ and T³ have the        meanings given above,    -   then removing one of the two ester groupings by heating with        lithium chloride in a DMSO/water mixture, then converting the        resulting 3-phenylpropionic ester of the formula (XXIII)

-   -   in which L, R³, R^(4A), R^(4B), R⁵, R⁶, R⁷ and T³ have the        meanings given above,    -   by reaction with nitronium tetrafluoroborate into the        3-nitrophenyl derivative of the formula (XXIV)

-   -   in which L, R³, R^(4A), R^(4B), R⁵, R⁶, R⁷ and T³ have the        meanings given above,    -   and finally hydrogenating in the presence of a suitable        palladium or platinum catalyst to give a        3-(3-aminophenyl)propionic ester of the formula (III-B)

-   -   in which L, R³, R^(4A), R^(4B), R⁵, R⁶, R⁷ and T³ have the        meanings given above,        or        [E-2] converting a protected 3-aminophenyl iodide of the formula        (XXV)

-   -   in which R⁶ and R⁷ have the meanings given above    -   and    -   PG represents benzyl or 4-methoxybenzyl as inert amino        protective group,    -   in an inert solvent with isopropylmagnesium chloride in the        presence of lithium chloride into the corresponding phenyl        magnesium compound, then coupling this compound in situ under        copper(I) catalysis with an alkylidenemalonic ester of the        formula (XXI)

-   -   in which L, R³, R^(4A), R^(4B), and R⁵ have the meanings given        above    -   and    -   T³ represents methyl or ethyl,    -   to give a compound of the formula (XXVI)

-   -   in which L, PG, R³, R^(4A), R^(4B), R⁵, R⁶, R⁷ and T³ have the        meanings given above,    -   then deprotecting this compound by hydrogenolysis or by        treatment with a suitable oxidizing agent such as, for example,        2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to give a        compound of the formula (XXVII)

-   -   in which L, R³, R^(4A), R^(4B), R⁵, R⁶, R⁷ and T³ have the        meanings given above,    -   and then removing one of the two ester groupings by heating with        lithium chloride in a DMSO/water mixture, to give the        3-(3-aminophenyl)propionic ester of the formula (III-B)

-   -   in which L, R³, R^(4A), R^(4B), R⁵, R⁶, R⁷ and T³ have the        meanings given above,        or        [F] alkylating a carboxylic eater of the formula (XXVII)

-   -   in which R¹, R² and T¹ have the meanings given above,    -   in an inert solvent after α-deprotonation with a 3-bromobenzyl        compound of the formula (XXIX)

-   -   in which L, R^(4A), R^(4B), R⁵, R⁶ and R⁷ have the meaning given        above    -   and    -   X² represents a suitable leaving group, such as chlorine,        bromine, iodine, mesylate, triflate or tosylate,    -   to give a compound of the formula (XXX)

-   -   in which L, R¹, R², R^(4A), R^(4B), R⁵, R⁶, R⁷ and T¹ have the        meanings given above,    -   then reacting with benzylamine in the presence of a base and a        palladium catalyst to give a compound of the formula (XXXI)

-   -   in which L, R¹, R², R^(4A), R^(4B), R⁵, R⁶, R⁷ and T¹ have the        meanings given above,    -   and then removing the N-benzyl group by hydrogenolysis, to give        a 3-(3-aminophenyl)propionic ester of the formula (III-C)

-   -   in which L, R¹, R², R^(4A), R^(4B), R⁵, R⁶, R⁷ and T¹ have the        meanings given above.

Suitable for deprotonating the phosphono ester (XI) in the olefinationreactions (XI)+(XII)→(XII) and (XI)+(XIV)→(XV) are in particularnon-nucleophilic strong bases such as, for example, sodium hydride orpotassium hydride, lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide orlithium diisopropylamide; preference is given to using sodium hydride.

The hydrogenation in the process steps (XIII)→(III-A), (XV)→(III-A),(XIX)→(III-A) and (XXIV)→(III-B) is generally carried out under astationary hydrogen atmosphere at atmospheric or elevated pressure. Thepreferred catalyst used is palladium or platinum on activated carbon (assupport material). The removal of the amino protective group(s) in thetransformations (XVI)→(III-A), (XXVI)→(XXVII) and (XXXI)→(III-C) isusually carried out by hydrogenolysis according to the same procedure;if PG in (XVI) or (XXVI) represents p-methoxybenzyl, this mayalternatively also be carried out oxidatively, for example with the aidof 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or ammoniumcerium(IV) nitrate.

Preferred for use as palladium catalyst for the reaction(XVII)+(XVIII)→(XIX) [Heck reaction] is palladium(II) acetate ortris(dibenzylideneacetone)dipalladium(0), in each case in combinationwith a phosphine ligand such as, for example, tritert-butylphosphine,triphenylphosphine or tri-2-tolylphosphine.

The conversion of the phenyl iodide (XX) into the correspondingphenylmagnesium compound and its copper(I)-mediated 1,4-addition to thealkylidenemlonate (XXI) to give the product of the formula (XXII) arecarried out by a general method known from the literature [see, forexample, P. Knochel et al., Tetrahedron 56, 2727-2731 (2000), and theliterature cited therein]; this also applies to the analogous reaction(XXV)+(XXI)→(XXVI).

Particularly suitable for the α-deprotonation of the carboxylic ester(XXVIII) in the alkylation reaction (XXVIII)+(XXIX)→(XXX) arenon-nucleophilic strong bases such as, for example, sodium tert-butoxideor potassium tert-butoxide, sodium hydride or potassium hydride, lithiumdiisopropylamide or lithium bis(trimethylsilyl)amide; sodiumbis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide;preference is given to using lithium diisopropylamide. Preferred inertsolvents for this reaction are ethers such as diethyl ether, diisopropylether, methyl tert-butyl ether, tetrahydrofuran, glycol dimethyl etheror diethylene glycol dimethyl ether. The reaction is usually carried outin a temperature range of from −80° C. to +25° C.

For the transformation (XXX)→(XXXI) [Buchwald-Hartwig coupling withbenzylamine], the preferred catalysttris(dibenzylideneacetone)dipalladium(0) in combination with(±)-2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl is phosphine ligand,and the preferred base is sodium tert-butoxide or potassiumtert-butoxide [cf., for example, J. P. Wolfe and S. L. Buchwald, OrganicSyntheses, Coll. Vol. 10, 423 (2004), Vol. 78, 23 (2002)].

The reactions described above can be carried out at atmosphericpressure, at elevated pressure or at reduced pressure (for example inthe range of from 0.5 to 5 bar); in general in each case carried out atatmospheric pressure.

Separation of the compounds according to the invention into thecorresponding enantiomer and/or diastereomers can take place whereappropriate, depending on expediency, even at the stage of the compounds(II), (III), (IV), (VII), (XVI), (XXII), (XXIII), (XXIV), (XXVI),(XXVII), (XXX) or (XXXI), which are then reacted further in separatedform in accordance with the above-described process sequences. Suchseparation of the isomers can be carried out by conventional methodsknown to a person skilled in the art. In the context of the presentinvention, preference is given to using chromatographic methods onachiral or chiral separation phases; in the case of carboxylic acids andas intermediates or end products, separation may alternatively also bevia diastereomeric salts.

The compounds of the formulae (V), (VI), (VIII), (IX), (XI), (XII),(XIV), (XVII), (XVIII), (XX), (XXI), (XXV), (XXVIII) and (XXIX) areeither commercially available or described as such in the literature, orthey can be prepared in a manner obvious to the person skilled in theart analogously to the methods published in the literature. Numerousdetailed procedures and literature references for preparing the startingmaterials can also be found in the Experimental Part in the section onthe preparation of the starting materials and intermediates.

The preparation of the compounds according to the invention can beillustrated in an exemplary manner by the reaction schemes below:

The compounds according to the invention have valuable pharmacologicalproperties and can be used for the prevention and treatment of disordersin humans and animals.

The compounds according to the invention are potent activators ofsoluble guanylate cyclase. They lead to vasorelaxation, inhibition ofplatelet aggregation and lowering of blood pressure and increase ofcoronary blood flow. These effects are mediated via directhaem-independent activation of soluble guanylate cyclase and an increaseof intracellular cGMP.

In addition, the compounds according to the invention have advantageouspharmacokinetic properties, in particular with respect to theirbioavailability and/or duration of action after intravenous or oraladministration.

The compounds according to the invention are particularly suitable forthe treatment and/or prevention of cardiovascular, pulmonary,thromboembolic and fibrotic disorders.

Accordingly, the compounds according to the invention can be used inmedicaments for the treatment and/or prevention of cardiovasculardisorders such as, for example, high blood pressure (hypertension),heart failure, coronary heart disease, stable and unstable anginapectoris, pulmonary arterial hypertension (PAH) and other forms ofpulmonary hypertension (PH), renal hypertension, peripheral andcardiovascular disorders, arrhythmias, atrial and ventriculararrhythmias and impaired conduction such as, for example,atrioventricular blocks degrees I-III, supraventricular tachyarrhythmia,atrial fibrillation, atrial flutter, ventricular fibrillation,ventricular flutter, ventricular tachyarrhythmia, Torsade de pointestachycardia, atrial and ventricular extrasystoles, AV-junctionalextrasystoles, Sick-Sinus syndrome, syncopes, AV-nodal re-entrytachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome(ACS), autoimmune cardiac disorders (pericarditis, endocarditis,valvolitis, aortitis, cardiomyopathies), boxer cardiomyopathy,aneurysms, shock such as cardiogenic shock, septic shock andanaphylactic shock, furthermore for the treatment and/or prevention ofthromboembolic disorders and ischaemias such as myocardial ischaemia,myocardial infarction, stroke, cardiac hypertrophy, transient andischaemic attacks, preeclampsia, inflammatory cardiovascular disorders,spasms of the coronary arteries and peripheral arteries, oedemaformation such as, for example, pulmonary oedema, cerebral oedema, renaloedema or oedema caused by heart failure, peripheral circulatorydisturbances, reperfusion damage, arterial and venous thromboses,microalbuminuria, myocardial insufficiency, endothelial dysfunction,microvascular and macrovascular damage (vasculitis), and also to preventrestenoses, for example alter thrombolysis therapies, percutaneoustransluminal angioplasties (PTA), percutaneous transluminal coronaryangioplasties (PTCA), heart transplants and bypass operations.

In the context of the present invention, the term heart failure includesboth acute and chronic manifestations of heart failure as well as morespecific or related types of disease, such as acute decompensated heartfailure, right heart failure, left heart failure, global failure,ischaemic cardiomyopathy, dilated cardiomyopathy, hypertrophiccardiomyopathy, idiopathic cardiomyopathy, congenital heart defects,heart valve defects, heart failure associated with heart valve defects,mitral stenosis, mitral insufficiency, aortic stenosis, aorticinsufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonaryvalve stenosis, pulmonary valve insufficiency, combined heart valvedefects, myocardial inflammation (myocarditis), chronic myocarditis,acute myocarditis, vital myocarditis, diabetic heart failure, alcoholiccardiomyopathy, cardiac storage disorders, and diastolic and systolicheart failure.

In addition, the compounds according to the invention can also beemployed for the treatment and/or prevention of arteriosclerosis, adisturbed lipid metabolism, hypolipoproteinaemias, dilipideamias,hypertriglyceridaemias, hyporipidaemias, combined hyperlipidaemias,hyper-cbolesterolaemias, abetalipoproteinaemias, sitosterolaemia,xanthomatosis, Tangier disease, adiposity, obesity and metabolicsyndrome.

Furthermore, the compounds according to the invention can be used forthe treatment and/or prevention of primary and secondary Raynaud'sphenomenon, of microcirculation impairments, claudication, tinnitus,peripheral and autonomic neuropathies, diabetic microangiopathies,diabetic retinopathy, diabetic ulcers on the extremities, gangrene,CREST syndrome, erythematosis, onychomycosis and rheumatic disorders.

In addition, the compounds according to the invention can be used forpreventing ischaemia- and/or reperfusion-related damage to organs ortissues and also as additives for perfusion and preservation solutionsof organs, organ parts, tissues or tissue parts of human or animalorigin, in particular for surgical interventions or in the field oftransplantation medicine.

The compounds according to the invention are furthermore suitable forthe treatment and/or prevention of kidney disorders, in particular ofrenal insufficiency and renal failure. In the context of the presentinvention, the term renal insufficiency and renal failure comprise bothacute and chronic manifestations thereof, as well as underlying orrelated kidney diseases such as renal hypoperfusion, intradialytichypotension, obstructive uropathy, glomerulopathies, glomerulonephritis,acute glomerulonephritis, gloreruloeclerosis, tubulointerstitialdiseases, nephropathic diseases such as primary and congenital kidneydisease, nephritis, immunological kidney diseases such as kidney graftrejection and immunocomplex-induced kidney diseases, nephropathy inducedby toxic substances, nephropathy induced by contrast agents, diabeticand non-diabetic nephropathy, pyelonephritis, renal cysts,nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome,which can be characterized diagnostically for example by abnormallyreduced creatinine and/or water excretion, abnormally raised bloodconcentrations of urea, nitrogen, potassium and/or creatinine, alteredactivity of renal enzymes such as, for example, glutamyl synthetase,altered urine osmolarity or urine volume, increased microalbuminurea,macroalbuminurea, lesions on glomerulae and arterioles, tubulardilatation, hyperphosphataemia and/or need for dialysis. The presentinvention also comprises the use of the compounds according to theinvention for the treatment and/or prevention of sequelae of renalinsufficiency, such as, for example hypertension, pulmonary oedema,heart failure, uraemia, anaemia, electrolyte disturbances (for examplehypercalaemia, hyponatraemia) and disturbances in bone and carbohydratemetabolism.

In addition, the compounds according to the invention are suitable forthe treatment and/or prevention of disorders of the urogenital systemsuch as, for example, benign prostate syndrome (BPS), benign prostatehyperplasia (BPH), benign prostate enlargement (BPE), bladder outletobstruction (BOO), lower urinary tract syndrome (LUTS), neurogenicoveractive bladder (OAB), incontinence such as, for example, mix, urge,stress or overflow incontinence (MUI, UUI, SUI, OUI), pelvic pain, andalso erectile dysfunction and female sexual dysfunction.

The compounds according to the invention are also suitable for thetreatment and/or prevention of asthmatic disorders, chronic-obstructivepulmonary disease (COPD), acute respiratory distress syndrome (ARDS) andacute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD),pulmonary fibrosis, pulmonary emphysema (for example pulmonary emphysemainduced by cigarette smoke) and cystic fibrosis (CF), and also ofpulmonary arterial hypertension (PAH) and other forms of pulmonaryhypertension (PH) including left-heart disease, HIV, sickle cellanaemia, thromboembolisms, sarcoidosis, COPD or pulmonaryfibrosis-associated pulmonary hypertension.

The compounds described in the present invention also represent activecompounds for controlling central nervous system diseases characterizedby disturbances of the NO/cGMP system. They are suitable in particularfor improving perception, concentration, learning or memory aftercognitive impairments like those occurring in particular in associationwith situations/diseases/syndromes such as mild cognitive impairment,age-associated learning and memory impairments, age-associated memoryloss, vascular dementia, craniocerebral trauma, stroke, dementiaoccurring after strokes (post-stroke dementia), post-traumaticcraniocerebral trauma, general concentration impairments, concentrationimpairments in children with learning and memory problems, Alzheimer'sdisease, Lewy body dementia, dementia with degeneration of the frontallobes including Pick's syndrome, Parkinson's disease, progressivenuclear palsy, dementia with corticobasal degeneration, amyolateralsclerosis (ALS), Huntington's disease, demyelinisation, multiplesclerosis, thalamic degeneration, Creutzfeld-Jakob dementia, HIVdementia, schizophrenia with dementia or Korsakoff's psychosis. They arealso suitable for the treatment and/or prevention of central nervoussystem disorders such as states of anxiety, tension and depression,CNS-related sexual dysfunctions and sleep disturbances, and forcontrolling pathological disturbances of the intake of food, stimulantsand addictive substances.

The compounds according to the invention are furthermore also suitablefor controlling cerebral blood flow and thus represent effective agentsfor controlling migraine. They are also suitable for the prophylaxis andcontrol of the sequelae of cerebral infarctions (Apoplexia cerebri) suchas stroke, cerebral ischaemias and craniocerebral trauma. The compoundsaccording to the invention can likewise be employed for controllingstates of pain.

In addition, the compounds according to the invention haveantiinflammatory action and can therefore be used as antiinflammatoryagents for the treatment and/or prevention of sepsis (SIRS), multipleorgan failure (MODS, MOF), inflammatory disorders of the kidney, chronicinflammation of the bowel (IBS, Crohn's disease, ulcerative colitis),pancreatitis, peritonitis, rheumatoid disorders, inflammatory skindiseases and inflammatory eye diseases.

The compounds according to the invention are furthermore suitable forthe treatment and/or prevention of fibrotic disorders of the internalorgans such as, for example, the lung, the heart, the kidney, the bonemarrow and in particular the liver, and also dermatological fibroses andfibrotic eye disorders. In the context of the present invention, theterm fibrotic disorders includes in particular the following disorders:hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis,endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitialrenal fibrosis, fibrotic damage resulting from diabetes, bone marrowfibrosis and similar fibrotic disorders, scleroderma, morphea, keloids,hypertrophic scarring, naevi, diabetic retinopathy, proliferativevitreoretinopathy and disorders of the connective tissue (for examplesarcoidosis). The compounds according to the invention can also be usedto promote wound healing, for controlling postoperative scarring, forexample as a result of glaucoma operations, and cosmetically for ageingand keratinized skin.

By virtue of their activity profile, the compounds according to theinvention are particularly suitable for the treatment and/or preventionof cardiovascular disorders such as heart failure, angina pectoris,hypertension and pulmonary hypertension, and also of thromboembolicdisorders and ischaemias, vascular disorders, disturbances ofmicrocirculation, renal insufficiency, fibrotic disorders andarteriosclerosis.

The present invention further relates to the use of the compoundsaccording to the invention for the treatment and/or prevention ofdisorders, especially of the aforementioned disorders.

The present invention further relates to the use of the compoundsaccording to the invention for producing a medicament for the treatmentand/or prevention of disorders, especially of the aforementioneddisorders.

The present invention further relates to the use of the compoundsaccording to the invention in a method for the treatment and/orprevention of disorders, especially of the aforementioned disorders.

The present invention further relates to a method for the treatmentand/or prevention of disorders, especially of the aforementioneddisorders, by using an effective amount of at least one of the compoundsaccording to the invention.

The compounds according to the invention can be employed alone or, ifrequired, in combination with other active compounds. The presentinvention further provides medicaments comprising at least one of thecompounds according to the invention and one or more further activecompounds, especially for the treatment and/or prevention of theaforementioned disorders. Preferred examples of suitable active compoundcombinations include:

-   -   organic nitrates and NO donors, for example sodium        nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide        dinitrate, molsidomine or SIN-1, and inhaled NO;    -   compounds which inhibit the breakdown of cyclic guanosine        monophosphate (cGMP), such as, for example, inhibitors of        phosphodiesterases (PDE) 1, 2 and/or 5, in particular PDE 5        inhibitors such as sildenafil, vardenafil and tadalafil;    -   NO-independent, but haem-dependent stimulators of guanylate        cyclase, such as, in particular, riociguat and the compounds        described in WO 00/06568, WO 00/06569, WO 02/42301 and WO        03/095451;    -   agents having an antithrombotic effect, for example and with        preference from the group of platelet aggregation inhibitors, of        anticoagulants or of profibrinolytic substances;    -   active compounds which lower blood pressure, for example and        preferably from the group of calcium antagonists, angiotensin        AII antagonists, ACE inhibitors, endothelin antagonists, renin        inhibitors, alpha-receptor blockers, beta-receptor blockers,        mineralocorticoid receptor antagonists, and of diuretics; and/or    -   active compounds which alter lipid metabolism, for example and        with preference from the group of thyroid receptor agonists,        cholesterol synthesis inhibitors such as, by way of example and        preferably, HMG-CoA reductase inhibitors or squalene synthesis        inhibitors, of ACAT inhibitors, CETP inhibitors, MTP inhibitors,        PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol        absorption inhibitors, lipase inhibitors, polymeric bile acid        adsorbents, bile acid reabsorption inhibitors and        lipoprotein (a) antagonists.

Agents having antithrombotic activity preferably mean compounds from thegroup of platelet aggregation inhibitors, of anticoagulants or ofprofibrinolytic substances.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a plateletaggregation inhibitor such as, by way of example and preferably,aspirin, clopidogrel, ticlopidin or dipyridamol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombin inhibitorsuch as, by way of example and preferably, ximelagatran, melagatran,dabigatran, bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a GPIIb/IIIaantagonist such as, by way of example and preferably, tirofiban orabciximab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a factor Xa inhibitorsuch as, by way of example and preferably, rivaroxaban, apixaban,fidexaban, zazaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112,YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with heparin or a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vitamin Kantagonist such as, by way of example and preferably, coumarin.

Agents which lower blood pressure are preferably understood to meancompounds from the group of calcium antagonists, angiotensin AIIantagonists, ACE inhibitors, eudothelin antagonists, renin inhibitors,alpha-receptor blockers, beta-receptor blockers, mineralocorticoidreceptor antagonists, and the diuretics.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcium antagonistsuch as, by way of example and preferably, nifedipine, amlodipine,verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alpha-1 receptorblocker such as, by way of example and preferably, prazosin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a beta receptorblocker such as, by way of example and preferably, propranolol,atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol,bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol,metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol,labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol orbucindolol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an angiotensin AIIantagonist such as, by way of example and preferably, losartan,candesartan, valsartan, telmisartan or embusartan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACE inhibitor suchas, by way of example and preferably, enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an endothelinantagonist such as, by way of example and preferably, bosentan,darusentan, ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a main inhibitor suchas, for example and preferably, aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a mineralocorticoidreceptor antagonist such as, for example and preferably, spironolactoneor eplerenone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a diuretic, such as,for example and preferably, furosemide, bumetanide, torsemide,bendroflumethiazide, chlorothiazide, hydrochlorothiazide,hydro-flumethiazide, methyclothiazide, polythiazide,trichloromethiazide, chlorthalidone, indapamide, metolazone,quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerol,isosorbide, mannitol, amiloride or triamterene.

Agents which alter lipid metabolism are preferably understood to meancompounds from the group of CETP inhibitors, thyroid receptor agonists,cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors orsqualene synthesis inhibitors, of ACAT inhibitors, MTP inhibitors,PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterolabsorption inhibitors, polymeric bile acid adsorbents, bile acidreabsorption inhibitors, lipase inhibitors and lipoprotein (a)antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CETP inhibitor suchas, by way of example and preferably, torcetrapib (CP-529 414), JJT-705or CETP vaccine (Avant).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thyroid receptoragonist such as, by way of example and preferably, D-thyroxin,3,5,3′-triiodothyronin (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an HMG-CoA reductaseinhibitor from the class of the statins such as, by way of example andpreferably, lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a squalene synthesisinhibitor such as, by way of example and preferably, BMS-188494 orTAK-475.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACAT inhibitorsuch as, by way of example and preferably, avasimibe, melinamide,pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an MTP inhibitor suchas, by way of example and preferably, implitapide, BMS-201038, R-103757or JTT-130.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-gamma agonistsuch as, by way of example and preferably, pioglitazone orrosiglitazone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-delta agonistsuch as, for example and preferably, GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cholesterolabsorption inhibitor such as, by way of example and preferably,ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipase inhibitorsuch as, by way of example and preferably, orlistat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a polymeric bile acidadsorbent such as, by way of example and preferably, cholestyramine,colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a bile acidreabsorption inhibitor such as, by way of example and preferably, ASBT(=IBAT) inhibitors, for example AZD-7806, S-8921, AK-105, BARI-1741,SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipoprotein (a)antagonist such as, by way of example and preferably, gemcabene calcium(CI-1027) or nicotinic acid.

The present invention further provides medicaments which comprise atleast one compound according to the invention, typically together withone or more inert, nontoxic, pharmaceutically suitable auxiliaries, andthe use thereof for the aforementioned purposes.

The compounds according to the invention may act systemically and/orlocally. For this purpose, they can be administered in a suitablemanner, for example by the oral, parenteral, pulmonal, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival,otic route, or as an implant or stent.

The compounds according to the invention can be administered inadministration forms suitable for these administration routes.

Suitable administration forms for oral administration are those whichwork according to the prior art, which release the compounds accordingto the invention rapidly and/or in a modified manner and which containthe compounds according to the invention in crystalline and/oramorphized and/or dissolved form, for example tablets (uncoated orcoated tablets, for example with gastric juice-resistant orretarded-dissolution or insoluble coatings which control the release ofthe compound according to the invention), tablets or films/wafers whichdisintegrate rapidly in the oral cavity, films/lyophilizates or capsules(for example hard or soft gelatin capsules), sugar-coated tablets,granules, pellets, powders, emulsions, suspensions, aerosols orsolutions.

Parenteral administration can bypass an absorption step (e.g.intravenously, intraarterially, intracardially, intraspinally orintralumbally) or include an absorption (e.g. intramuscularly,subcutaneously, intracutaneously, percutaneously or intraperitoneally).Administration forms suitable for parenteral administration includepreparations for injection and infusion in the form of solutions,suspensions, emulsions, lyophilizates or sterile powders.

For the other administration routes, suitable examples are inhalablemedicament forms (including powder inhalers, nebulizers), nasal drops,solutions or sprays, tablets, films/wafers or capsules for lingual,sublingual or buccal administration, suppositories, ear or eyepreparations, vaginal capsules, aqueous suspensions (lotions, shakingmixtures), lipophilic suspensions, ointments, creams, transdermaltherapeutic systems (e.g. patches), milk, pastes, foams, sprinklingpowders, implants or stents.

Oral or parenteral administration is preferred, especially oral andintravenous administration.

The compounds according to the invention can be converted to theadministration forms mentioned. This can be done in a manner known perse, by mixing with inert, nontoxic, pharmaceutically suitableexcipients. These excipients include carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (e.g. liquidpolyethylene glycols), emulsifiers and dispersing or wetting agents (forexample sodium dodecylsulphate, polyoxysorbitan oleate), binders (forexample polyvinylpyrrolidone), synthetic and natural polymers (forexample albumin), stabilizers (e.g. antioxidants, for example ascorbicacid), dyes (e.g. inorganic pigments, for example iron oxides) andflavour and/or odour correctants.

In general, it has been found to be advantageous in the case ofparenteral administration to administer amounts of about 0.001 to 1mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to achieveeffective results. In the case of oral administration, the dosage isabout 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and mostpreferably 0.1 to 10 mg/kg of body weight.

It may nevertheless be necessary where appropriate to deviate from thestated amounts, specifically as a function of the body weight, route ofadministration, individual response to the active compound, nature ofthe preparation and time or interval over which administration takesplace. For instance, in some cases, less than the aforementioned minimumamount may be sufficient, while in other cases the upper limit mentionedmust be exceeded. In the case of administration of relatively largeamounts, it may be advisable to divide these into several individualdoses over the course of the day.

The working examples which follow illustrate the invention. Theinvention is not limited to the examples.

The percentages in the tests and examples which follow are, unlessindicated otherwise, percentages by weight; parts are parts by weight.Solvent ratios, dilution ratios and concentration data for liquid/liquidsolutions are based in each case on volume.

A. EXAMPLES Abbreviations and Acronyms

-   abs. absolute-   Ac acetyl-   AIBN 2,2′-azobis-(2-methylpropionitrile)-   aq. aqueous, aqueous solution-   ATP adenosine 5′-triphosphate-   Bn benzyl-   Brij® polyethylene glycol dodecyl ether-   BSA bovine serum albumin-   Ex. example-   Bu butyl-   c concentration-   cat. catalytic-   CI chemical ionization (in MS)-   d day(s)-   DAST diethylaminosulphur trifluoride-   DC thin-layer chromatography-   DCI direct chemical ionization (in MS)-   DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone-   de diastereomeric excess-   DMF dimethylformamide-   DMSO dimethyl sulphoxide-   DTT dithiothreitol-   EDC N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride-   ee enantiomeric excess-   EI electron impact ionization (in MS)-   ent enantiomerically pure, enantiomer-   eq. equivalent(s)-   ESI electrospray ionization (in MS)-   Et ethyl-   GC gas chromatography-   sat. saturated-   GTP guanosine 5′-triphosphate-   h hour(s)-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBt 1-hydroxy-1H-benzotriazole hydrate-   HPLC high pressure, high performance liquid chromatography-   iPr isopropyl-   conc. concentrated-   LC-MS liquid chromatography-coupled mass spectroscopy-   LDA lithium diisopropylamide-   LiHMDS lithium hexamethyldisilazide [lithium    bis(trimethylsilyl)amide]-   Me methyl-   min minute(s)-   MS mass spectroscopy-   NBS N-bromosuccinimide-   NMP N-methylpyrrolidin-2-one-   NMR nuclear magnetic resonance spectroscopy-   p para-   Pd/C palladium on activated carbon-   Ph phenyl-   PMB p-methoxybenzyl-   Pr Propyl-   Pt/c platinum on activated carbon-   rac racemic, racemate-   R_(f) retention index (in TLC)-   RP reverse phase (in HPLC)-   RT room temperature-   R_(t) retention time (in HPLC or GC)-   tBu tert-butyl-   TEA triethanolamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   UV ultraviolet spectroscopy-   v/v ratio by volume (of a solution)    GC-MS and LC-MS Methods:    Method 1 (GC-MS):

Instrument: Micronmss GT, GC 6890; column: Restek RTX-35, 15 m×200μm×0.33 μm; constant helium flow: 0.88 ml/min; oven: 70° C.; inlet: 250°C.; gradient: 70° C., 30° C./min→310° C. (maintained for 3 min).

Method 2 (LC-MS):

MS instrument type: Waters Micromass Quattro Micro; HPLC instrumenttype: Agilent 1100 Series; column: Thermo Hypersil GOLD 3μ 20 mm×4 mm;mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobilephase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid;gradient: 0.0 min 100% A→3.0 min 10% A→4.0 min 10% A→4.01 min 100% A(flow rate 2.5 ml/min)→5.00 min 100% A; oven: 50° C.; flow rate: 2ml/min; UV detection: 210 nm.

Method 3 (LC-MS):

MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 Series;UV DAD; column: Phenomenex Gemini 3μ 30 mm×3.00 mm; mobile phase A: 1 lof water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90%A→25 min 30% A→3.0 min 5% A→4.5 min 5% A; flow rate: 0.0 min 1ml/min→2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 210nm.

Method 4 (LC-MS):

Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column:Thermo Hypersil GOLD 1.9μ 50 mm×1 mm; mobile phase A: 1 l of water+0.5ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5ml of 50% strength formic acid; gradient: 0.0 min 90% A→0.1 min 90%A→1.5 min 10% A→2.2 min 10% A; flow rate: 0.33 ml/min; oven: 50° C.; UVdetection: 210 nm.

Method 5 (LC-MS):

Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8μ, 50 mm×1 mm; mobile phase A: 1 l of water+0.25 ml of 99%strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99%strength formic acid; gradient: 0.0 min 90% A→1.2 min 5% A→2.0 min 5% A;flow rate: 0.40 ml/min; oven: 50° C.; UV detection: 210-400 nm.

Method 6 (GC-MS):

Instrument: Thermo DFS, Trace GC Ultra; column: Restek RTX-35, 15 m×200μm×0.33 μm; constant helium flow: 1.20 ml/min; oven: 60° C.; inlet: 220°C.; gradient: 60° C., 30° C./min→300° C. (maintained for 3.33 min).

Method 7 (LC-MS):

Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8μ, 30 mm×2 mm; mobile phase A: 1 l of water+0.25 ml of 99%strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99%strength formic acid; gradient: 0.0 min 90% A→1.2 min 5% A→2.0 min 5% A;flow rate: 0.60 ml/min; oven: 50° C.; UV detection: 208-400 nm.

Method 8 (LC-MS):

Instrument: Micromass Quattro Premier with Waters UPLC Acquity, column:Thermo Hypersil GOLD 1.9μ 50 mm×1 mm; mobile phase A: 1 l of water+0.5ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5ml of 50% strength formic acid; gradient: 0.0 min 97% A→0.5 min 97%A→3.2 min 5% A→4.0 min 5% A; flow rate: 0.3 ml/min; oven: 50° C.; UVdetection: 210 nm.

Starting Materials and Intermediates Example 1A tert-Butyl(2E/Z)-4-methoxy-4-methylpent-2-enoate

At −70° C. and under argon, 6.8 ml (96 mmol) of DMSO in 10 ml ofdichloromethane were added dropwise to a mixture of 24 ml (48 mmol) of a2 M solution of oxalyl chloride in dichloromethane and a further 100 mlof dichloromethane, and the mixture was stirred for 15 minutes. 5.2 ml(48 mmol) of 2-methoxy-2-methylpropan-1-ol [H. Garcia et al., Chem. Eur.J. 16 (28), 8530-8536 (2010)], dissolved in 15 ml of dichloromethane,were then added dropwise, and the mixture was stirred at −70° C. foranother 15 min. 22.1 ml (158 mmol) of triethylamine were added slowly,and the reaction mixture was then stirred for another 15 min andsubsequently slowly warmed to room temperature. 22 g (58 mmol) oftert-butyl (triphenyl-λ⁵-phosphanylidene)acetate were then added, andthe reaction mixture was stirred at room temperature overnight. Thereaction solution was then slowly added to 100 ml of ice-water, and thephases obtained were separated. The organic phase was washed twice within each case 100 ml of water, dried over magnesium sulphate andconcentrated under reduced pressure on a rotary evaporator (water bathtemperature 40° C., pressure not below 150 mbar). The residue obtainedwas taken up in about 100 ml of diethyl ether and allowed to stand in afridge at +3° C. for 2 days. The precipitated triphenylphosphine oxidewas filtered off, and the filtrate was concentrated under reducedpressure. The residue obtained was purified by chromatography on silicagel (mobile phase cyclohexane/ethyl acetate 100:1→50:1). This gave 7.06g (73% of theory) of the title compound as a colourless liquid.

GC-MS (method 6): R_(t)=3.32 min, m/z=218 (M+NH₄)⁺.

The two compounds below were obtained analogously to synthesis Example1A:

Example Name/Structure/Starting materials Analytical data 2A tert-butyl(2E)-3-(3,3-difluorocyclobutyl)acrylate  

  from tert-butyl (triphenyl-λ⁵-phosphanylidene)- acetate and(3,3-difluorocyclobutyl)methanol [CAS Reg. No. 681128-39-2] ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 1.42 (s, 9H), 2.48- 2.64 (m, 2H, partiallyobscured by DMSO signal), 2.70-2.84 (m, 2H), 2.90-3.04 (m, 1H), 5.84 (d,1H, ³J = 16.38 Hz), 6.86 (dd, 1H). 3A tert-butyl(2E)-4-cyclopropylbut-2-enoate  

  from tert butyl (triphenyl-λ⁵-phosphanylidene)- acetate and2-cyclopropylethanol GC-MS (Method 6): R_(t) = 3.42 min, m/z = 200 (M +NH₄)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.04-0.02 (m, 2H),0.33-0.40 (m, 2H), 0.63-0.75 (m, 1H), 1.34 (s, 9H), 1.94-2.00 (m, 2H),5.69-5.76 (m, 1H), 6.69- 6.79 (m, 1H).

Example 4A and Example 5A Methyl(2E/Z)-3-(3-amino-4-chlorophenyl)-4-methylpent-2-enoate and methyl3-(3-amino-4-chlorophenyl)-4-methylpent-3-enoate

Under argon, a mixture of 3.22 g (15.6 mmol) of 5-bromo-2-chloroaniline,3.0 g (23.4 mmol) of methyl-(2E)-4-methylpent-2-enoate, 143 mg (0.16mmol) of tris(dibenzylideneacetone)-dipalladium, 63 mg (0.31 mmol) oftri-ter-butylphosphine and 3.64 ml (17.2 mmol) ofN,N-dicyclohexylmethylamine in 30 ml of dioxane were heated to 120° C.and stirred at this temperature for three days. Both after the first andafter the second day of the reaction, the same amount of palladiumcatalyst and phosphine ligand was added to the reaction mixture. Thereaction mixture was then filtered through Celite, and the filtrate wasconcentrated under reduced pressure. The residue was separated into itscomponents by chromatography on silica gel (mobile phasecyclohexane/ethyl acetate 50:1). This gave 1.52 g of methyl(2E/Z)-3-(3-amino-4-chlorophenyl)-4-methylpent-2-enoate (38% of theory)and 906 mg of methyl 3-(3-amino-4-chlorophenyl)-4-methylpent-3-enoate(22% of theory).

Example 4A Methyl(2E/Z)-3-(3-amino-4-chlorophenyl)-4-methylpent-2-enoate

LC-MS (Method 2): R_(t)=2.46 min, m/z=254 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.03 (d, 6H), 3.65 (s, 3H), 3.90-4.03(m, 1H), 5.42 (br. s, 2H), 5.63 (s, 1H), 6.40 (dd, 1H), 6.69 (d, 1H),7.16 (d, 1H).

Example 5A Methyl 3-(3-amino-4-chlorophenyl)-4-methylpent-3-enoate

LC-MS (Method 2): R_(t)=2.28 man, m/z=254 (M+H)⁺.

The following compound was obtained analogously to Synthesis Example4A/5A:

Ex- Analytical ample Name/Structure/Starting materials data 6Atert-butyl (2E/Z)-3-(3-amino-4-chlorophenyl)-4-methoxy-4-methylpent-2-enoate  

  from tert-butyl (2E/Z)-4-methoxy-4-methylpent- 2-enoate and5-bromo-2-chloroaniline LC-MS (Method 5): R_(t) = 1.25 min, m/z =326/328 (M + H)⁺.

Example 7A tert-Butyl (2E)-3-cyclobutylacrylate

Step 1:

A solution of 11.1 ml (116.1 mmol) of oxalyl chloride in 50 ml of abs.dichloromethane was cooled to −78° C., and a solution of 16.5 ml (232.2mmol) of DMSO in 50 ml of abs. dichloromethane was added dropwise,keeping the temperature below −50° C. After 5 min, a solution of 10.0 g(116.1 mmol) of cyclobutanemethanol in 20 ml of abs. dichloromethane wasadded dropwise. After a further 15 min of stirring at −78° C., 80.9 ml(580.5 mmol) of triethylamine were added. After 5 min, cooling wasremoved and the mixture was slowly warmed to RT, and the reactionmixture was then added to water. The mixture was saturated with sodiumchloride and the separated organic phase was washed twice with saturatedsodium chloride solution, three times with 1 N hydrochloric acid andthree times with pH buffer solution, dried over sodium sulphate andconcentrated under reduced pressure (500 mbar). This gave 6.28 g ofcyclobutanecarbaldehyde as a crude product which was directly reactedfurther.

Step 2:

6.4 ml (27.3 mmol) of tert-butyl (diethoxyphosphoryl)acetate were addeddropwise to a suspension, cooled to 0° C., of 1.05 g (60% in mineraloil, 26.2 mmol) of sodium hydride in a mixture of 22 ml of THF and 22 mlof DMF. After 30 min, the mixture was cooled to −10° C., and 2.0 g(crude, about 23.8 mmol) of cyclobutanecarbaldehyde were added inseveral portions. The reaction mixture was stirred at 0° C. for 5 h andthen slowly warmed to RT overnight, subsequently added to water andextracted three times with ethyl acetate. The organic phases werecombined and concentrated under reduced pressure. The residue waspurified by chromatography on silica gel (mobile phase cyclohexane/ethylacetate 50:1). This gave 1.21 g of the target product (about 28% oftheory).

GC-MS (Method 1): R_(t)=3.26 min; m/z=126 (M−C₄H₈)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.42 (s, 9H), 1.74-1.96 (m, 4H),2.05-2.17 (m, 2H), 3.03-3.16 (m, 1H), 5.66 (dd, 1H), 6.86 (dd, 1H).

Example 8A and Example 9A tert-Butyl3-(3-amino-4-chlorophenyl)-3-cyclobutylacrylate and tert-butyl3-(3-amino-4-chlorophenyl)-3-cyclobutylidenepropanoate

0.78 ml (5.60 mmol) of triethylamine was added to a mixture of 385.2 mg(1.87 mmol) of 5-bromo-2-chloroaniline and 510 mg (2.80 mmol) oftert-butyl (2E)-3-cyclobutylacrylate in 2.8 ml of DMF. The mixture wasevacuated three times and in each case vented with argon. After theaddition of 41.9 mg (0.187 mmol) of palladium(II) acetate and 113.6 mg(0.373 mmol) of tri-2-tolylphosphine, the reaction mixture was evacuatedtwo more times and in each case vented with argon and then stirred at150° C. for 3 h. A further 193 mg of 5-bromo-2-chloroaniline were thenadded, and the reaction mixture was stirred at 150° C. for another 1 h.After cooling, the reaction mixture was filtered through Celite and thefilter residue was washed twice with DMF. The combined filtrate wasconcentrated under high vacuum, and by chromatography on silica gel(mobile phase cyclohexane/ethyl acetate 60:1) the two isomeric targetproducts were isolated from the residue. This gave 203 mg of tert-butyl3-(3-amino-4-chlorphenyl)-3-cyclobutylacrylate (35.4% of theory) and 137mg of tert-butyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylidenepropanoate(23.8% of theory).

Example 8A tert-Butyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylacrylate

LC-MS (Method 5): R_(t)=1.36 min, m/z=308 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.45 (s, 9H), 1.52-1.63 (m, 1H),1.74-1.85 (m, 3H), 2.09-2.18 (m, 2H), 4.10 (quin, 1H), 5.35-5.41 (m,2H), 5.55 (d, 1H), 6.38 (dd, 1H), 6.66 (d, 1H), 7.16 (d, 1H).

Example 9A tert-Butyl3-(3-amino-4-chlorophenyl)-3-cyclobutylidenpropanoate

LC-MS (Method 5): R_(t)=1.27 min, m/z=252 (M+H−C₄H₈)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.31 (s, 9H), 1.93 (quin, 2H),2.72-2.86 (m, 4H), 3.12 (s, 2H), 5.18-5.24 (m, 2H), 6.42 (dd, 1H), 6.69(d, 1H), 7.06-7.11 (m, 1H).

The following compounds were obtained analogously to Synthesis Example8A/9A:

Example Name/Structure/Starting materials Analytical data 10A tert-butyl(2E/Z)-3-(3-amino-4-chlorophenyl)- 3-(3,3-difluorocyclobutyl)acrylate  

  from tert-butyl (2E)-3-(3,3-difluorocyclobutyl)- acrylate and5-bromo-2-chloroaniline ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.46 (s,9H), 2.23- 2.41 (m, 2H), 2.77-2.90 (m, 2H), 3.88-4.01 (m, 1H), 5.45 (br.s, 2H), 5.73 (d, 1H), 6.41 (dd, 1H), 6.66 (d, 1H), 7.19 (d, 1H). LC-MS(Method 7): R_(t) = 1.37 min, m/z = 344 (M + H)⁺. 11A tert-butyl3-(3-amino-4-chlorophenyl)- 3-(3,3-difluorocyclobutylidene)propanoate  

  from tert-butyl (2E)-3-(3,3-difluorocyclobutyl)- acrylate and5-bromo-2-chloroaniline ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.31 (s,9H), 3.24 (s, 2H), 3.32-3.47 (m, 4H, partially obscured by H₂O signal),5.30 (br. s, 2H), 6.46 (dd, 1H), 6.74 (d, 1H), 7.13 (d, 1H). LC-MS(Method 7): R_(t) = 1.28 min, m/z = 344 (M + H)⁺. 12A tert-butyl(2E/Z)-3-(3-amino-4-chlorophenyl)- 4-cyclopropylbut-2-enoate  

  from tert-butyl (2E)-4-cyclopropylbut-2-enoate and5-bromo-2-chloroaniline 1H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.05-0.11(m, 2H), 0.27-0.34 (m, 2H), 0.64-0.75 (m, 1H), 1.45 (s, 9H), 2.91 (d,2H), 5.42 (br. s, 2H), 5.84 (s, 1H), 6.70 (dd, 1H), 6.96 (d, 1H), 7.19(d, 1H). LC-MS (Method 5): R_(t) = 1.35 min, m/z = 308 (M + H)⁺.

Example 13A Methyl 3-(3-amino-4-chlorophenyl)-4-methylpentanoate

At RT, a solution of 6.77 g (26.7 mmol) of methyl2E/Z)-3-(3-amino-4-chlorophenyl)-4-methylpent-2-enoate in 130 ml ofmethanol was added to 2.2 g (90.7 mmol) of magnesium turnings and a fewgrains of iodine. After about 30 min, the internal temperature increasedto about 60° C. After the reaction solution had cooled to roomtemperature, stirring at room temperature was continued for another 2 h,50 ml of saturated aqueous ammonium chloride solution were then addedslowly to the dark reaction mixture, and the mixture was extractedrepeatedly with diethyl ether. The combined organic phases were washedwith saturated sodium bicarbonate solution and saturated sodium chloridesolution, dried over magnesium sulphate and concentrated under reducedpressure. The residue obtained was purified by chromatography on silicagel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 2.95 g (40%of theory) of the title compound as an oil.

LC-MS (Method 5): R_(t)=1.06 min; m/z=256 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.69 (d, 3H), 0.87 (d, 3H), 1.67-1.80(m, 1H), 2.44-2.56 (m, 1H, obscured by DMSO signal), 2.57-2.66 (m, 1H),2.69-2.77 (m, 1H), 3.46 (s, 3H), 5.15-5.26 (br, 2H), 6.35 (dd, 1H), 6.58(d, 1H), 7.05 (d, 1H).

The following compounds were obtained analogously to Synthesis Example13A:

Example Name/Structure/Starting material Analytical data 14A tert-butyl3-(3-amino-4-chlorophenyl)-4-methoxy- 4-methylpentanoate  

  from tert-butyl (2E/Z)-3-(3-amino-4-chlorophenyl)-4-methoxy-4-methylpent-2-enoate LC-MS (Method 7): R_(t) = 1.26 min, m/z= 328/330 (M + H)⁺. 15A tert-butyl 3-(3-amino-4-chlorophenyl)-3-(3,3-difluorocyclobutyl)propanoate  

  from tert-butyl (2E/Z)-3-(3-amino-4-chlorophenyl)-3-(3,3-difluorocyclobutyl)acrylate ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =1.24 (s, 9H), 1.99- 2.17 (m, 1H), 2.19-2.40 (m, 4H), 2.46-2.57 (m, 1H,partially obscured by DMSO signal), 2.59-2.72 (m, 1H), 2.72-2.83 (m,1H), 5.24 (br. s, 2H), 6.42 (dd, 1H), 6.63 (d, 1H), 7.07 (d, 1H). LC-MS(Method 7): R_(t) = 1.28 min, m/z = 346 (M + H)⁺. 16A tert-butyl3-(3-amino-4-chlorophenyl)- 4-chloropropylbutanoate  

  from tert-butyl (2E/Z)-3-(3-amino-4-chlorophenyl)-4-cyclopropylbut-2-enoate LC-MS (Method 5): R_(t) = 1.32 min, m/z = 310(M + H)⁺.

Example 17A and Example 18A Methyl3-(3-amino-4-chlorophenyl)-4-methylpentanoate (enantiomers 1 and 2)

By preparative HPLC on a chiral phase, 960 mg (3.75 mmol) of theracemate of methyl 3-(3-amino-4-chlorophenyl)-4-methylpentanoate(Example 13A) were separated into the enantiomers [column: DaicelChiralpak AD-H, 5 μm, 250 mm×20 mm; mobile phase: isohexane/isopropanol90:10 (v/v); flow rate: 20 ml/min; UV detection: 230 n; temperature: 25°C.]:

Example 17A (Enantiomer 1)

Yield: 315 mg

R_(t)=6.90 min; chemical purity >99%; >99% e

[Column: Daicel AD-H, 5 μm, 250 mm×4 mm; mobile phase:isohexane/(isopropanol+0.2% diethylamine) 90:10 (v/v); flow rate: 1ml/min; UV detection: 220 nm; temperature: 25° C.].

LC-MS (Method 8): R_(t)=2.34 min; m/z=256 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.69 (d, 3H), 0.87 (d, 3H), 1.67-1.80(m, 1H), 2.44-2.56 (m, 1H, obscured by DMSO signal), 2.57-2.66 (m, 1H),2.69-2.77 (m, 1H), 3.46 (s, 3H), 5.15-5.26 (br. s, 2H), 6.35 (dd, 1H),6.58 (d, 1H), 7.05 (d, 1H).

Example 18A (Enantiomer 2)

Yield: 247 mg

R_(t)=7.76 min; chemical purity >99%; >99% ee

[Column: Daicel AD-H, S mm, 250 mm×4 mm; mobile phase:isohexane/(isopropanol+0.2% diethylamine) 90:10 (v/v); flow rate: 1ml/min; UV detection: 220 nm; temperature: 25° C.].

LC-MS (Method 8): R_(t)=2.34 min; m/z=256 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.69 (d, 3H), 0.87 (d, 3H), 1.67-1.80(m, 1H), 2.44-2.56 (m, 1H, obscured by DMSO signal), 2.57-2.66 (m, 1H),2.69-2.77 (m, 1H), 3.46 (s, 3H), 5.15-5.26 (br. s, 2H), 6.35 (dd, 1H),6.58 (d, 1H), 7.05 (d, 1H).

Example 19A 2-Chloro-5-iodo-N,N-bis(4-methoxybenzyl)aniline

Under argon, 12.62 g (316.16 mmol, 60% in mineral oil) of sodium hydridewere suspended in 250 ml of abs. DMF and cooled to 0° C. 32 g (126.3mmol) of 2-chloro-5-iodoaniline, dissolved in 80 ml of abs. DMF, werethen slowly added dropwise, and the mixture was stirred at 0° C. for 30min. 41 ml (303 mmol) of1-(chloromethyl)-4-methoxybenzene were thenslowly added to the reaction mixture, and the mixture was subsequentlywarmed to room temperature. The mixture was stirred at RT overnight andthen carefully poured into 150 ml of ice-water. The organic phase wasseparated off, and the aqueous phase was then extracted three more timeswith diethyl ether. The combined organic phases were dried overmagnesium sulphate. After filtration, the solvent was removed underreduced pressure. The crude product obtained was purified bychromatography on silica gel (mobile phase cyclohexane/ethyl acetate40:1). This gave 59 g of the title compound (94% of theory).

LC-MS (Method 4): R_(t)=1.77 min; m/z=494/496 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=3.71 (s, 6H), 4.08 (s, 4H), 6.86 (d,4H), 7.22 (d, 5H), 7.29-7.35 (m, 2H).

Example 20A{3-[Bis(4-methoxybenzyl)amino]-4-chlorophenyl}(1-methylcyclopropyl)methanone

Under argon, 7.587 g (15.37 mmol) of2-chloro-5-iodo-N,N-bis(4-methoxybenzyl)aniline were dissolved in 100 mlof THF and cooled to −78° C., 7.65 ml (15.27 mmol) of a 2 M solution ofisopropylmagnesium chloride in diethyl ether were then slowly addeddropwise. The reaction solution was then slowly warmed to −40° C. andstirred at this temperature for 30 min. 2 g (13.97 mmol) ofN-methoxy-N,1-dimehylcyclopropanecarboxamide [R. R. Shintani et al,Chem. Eur. J., 15 (35), 8692-8694 (2009)], dissolved in 20 ml of THF,were then slowly added dropwise to the reaction solution. The reactionmixture obtained was then slowly warmed to room temperature and stirredat this temperature overnight. 50 ml of an ice-cold saturated aqueousammonium chloride solution were then added to the reaction mixture.After separation of the phases, the aqueous phase was extracted threemore times with ethyl acetate, and the combined organic phases weredried over magnesium sulphate, filtered and evaporated to dryness. Thecrude product obtained was purified chromatographically on silica gel(mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.977 g (63% oftheory) of the title compound.

LC-MS (Method 5): R_(t)=1.50 min m/z=450/452 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.72-0.76 (m, 2H), 0.93-0.98 (m, 2H),1.09 (s, 3H), 3.69 (s, 6H), 4.15 (s, 4H), 6.85 (d, 4H), 7.23 (d, 4H),7.25-7.29 (m, 2H), 7.52-7.57 (m, 1H).

Example 21A tert-Butyl(2E/Z)-3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-3-(1-methylcyclopropyl)-acrylate

0.84 ml (3.57 mmol) of ten-butyl (diethoxyphosphoryl)acetate was addeddropwise to a suspension, cooled to 0° C., of 143 mg (60% in mineraloil, 3.57 mmol) of sodium hydride in 15 ml of THF. After 30 min, 1070 mg(2.38 mmol) of{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}(1-methylcyclopropyl)methanone,dissolved in 10 ml of THF, were added. The cooling bath was removed, andthe reaction mixture was stirred at RT overnight. 50 ml of an ice-coldsaturated aqueous ammonium chloride solution were then added to thereaction mixture. After separation of the phases, the aqueous phase wasextracted three more times with ethyl acetate, and the combined organicphases were dried over magnesium sulphate, filtered and evaporated todryness. The residue was purified by chromatography on silica gel(mobile phase cyclohexane/ethyl acetate 50:1). This gave 960 mg of thetarget product as an E/Z isomer mixture (74% of theory).

LC-MS (Method 7): R_(t)=1.67 min (isomer 1), m/z=548/550 (M+H)⁺;R_(t)=1.70 min (isomer 2), m/z=548/550 (M+H)⁺.

Example 22A tert-Butyl3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-3-(1-methylcyclopropyl)propenoate

130 mg (1.58 mmol) of magnesium turnings and a few grains of iodine wereinitially charged, 865 mg (1.58 mmol) of tert-butyl(2E/Z)-3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-3-(1-methylcyclopropyl)acrylatein 10 ml of methanol were added and the mixture was stirred at roomtemperature. After about 10 min, there was a weak evolution of gascombined with a temperature increase. Using an ice bath, the temperaturewas kept at 35°-40° C. After the reaction had ended, 10 ml of asaturated aqueous ammonium chloride solution and 20 ml ofdichloromethane were added to the reaction mixture. The organic phasewas then separated off and the aqueous phase was extracted three moretimes with in each case about 10 ml of dichloromethane. The combinedorganic phases were dried over magnesium sulphate and concentrated underreduced pressure. The product was isolated from the residue bypreparative RP-HPLC (mobile phase methanol/water 9:1 isocratic). Thisgave 159 mg of the target product (18% of theory).

LC-MS (Method 4): R_(t)=1.91 min; m/z=550/552 (M+H)⁺.

Example 23A tert-Butyl3-(3-amino-4-chlorophenyl)-3-(1-methylcyclopropyl)propanoate

159 mg (0.29 mmol) of tert-butyl3-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-3-(1-methylcyclopropyl)propanoatewere taken up in 7 ml of dichloromethane and 1.2 ml of water. 145 mg(0.64 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) were thenadded, and the reaction solution was stirred at room temperature for 2h. The reaction mixture was than added to 10 ml of saturated aqueoussodium bicarbonate solution. The phases were separated, and the aqueousphase was then extracted three more times with in each case about 10 mlof dichloromethane. The combined organic phases were dried overmagnesium sulphate and concentrated under reduced pressure. The productwas isolated from the residue by preparative RP-HPLC (mobile phasemethanol/water). This gave 31 mg of the target product (34% of theory).

LC-MS (Method 7): R_(t)=1.35 min; m/z=310 (M+H)⁺.

Example 24A (4-Chloro-3-nitrophenyl)(cyclopropyl)methanone

Under argon and at −10° C., 20 g (110.7 mmol) of(4-chlorophenyl)(cyclopropyl)methanone were added slowly to 60 ml ofconcentrated nitric acid. The reaction mixture was then slowly warmed to5° C. and stirred at this temperature for 6 h. Carefully, the reactionsolution was then added with stirring to about 100 ml of ice-water. Thisresulted in the precipitation of a white solid which was filtered offwith suction and washed repeatedly with water. The solid obtained inthis manner was then dried under high vacuum. This gave 24.3 g (97% oftheory) of the desired product.

LC-MS (Method 7): R_(t)=1.06 min; m/z=224/226 (M−H)⁻.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.05-1.18 (m, 4H), 2.92-3.02 (m, 1H),7.97 (d, 1H), 8.32 (dd, 1H), 8.66 (d, 1H).

The following compound was obtained analogously to Synthesis Example24A:

Example Name/Structure/Starting material Analytical data 25A(4-chloro-3-nitrophenyl)(1- fluorocyclopropyl)-methanone  

  from (4-chlorophenyl)(1-fluorocyclopropyl)- methanone [preparationaccording to DE 3704262-A1, Example (II-1)] LC-MS (Method 7): R_(t) =1.11 min, m/z = 242 (M − H)⁻.

Example 26A tert-Butyl(2E/Z)-3-(4-chloro-3-nitrophenyl)-3-cyclopropylacrylate

13.5 ml (57.6 mmol) of tert-butyl (diethoxyphosphoryl)acetate were addeddropwise to a suspension, cooled to 0° C., of 2.3 g (60% in mineral oil,57.6 mmol) of sodium hydride in 50 ml of THF and 50 ml of DMF. After 30min, 10 g (44.3 mmol) of (4-chloro-3-nitrophenyl)-(cyclopropyl)methanonewere added a little at a time, the cooling bath was removed and thereaction mixture was stirred at RT overnight. 50 ml of an ice-cooledsaturated aqueous ammonium chloride solution were then added to thereaction mixture. After separation of the phases, the aqueous phase wasextracted three more times with ethyl acetate and the combined organicphases were dried over magnesium sulphate, filtered and concentrated todryness. The residue was purified by chromatography on silica gel(mobile phase cyclohexane→cyclohexane/ethyl acetate 40:1). This gave13.4 g of the target product as an E/Z isomer mixture (93% of theory).

MS (DCI): m/z=324 (M+H)⁺, 341 (M+NH₄)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.32-0.39 (m, 0.5H), 0.51-0.58 (m,1.5H), 0.79-0.87 (m, 1.5H), 0.88-0.96 (m, 0.51), 1.17 (s, 6.75H), 1.47(s, 2.25H), 1.73-1.82 (m, 0.75H), 2.81-2.90 (m, 0.25H), 5.84 (s, 0.25H),5.88 (s, 0.75H), 7.43 (dd, 0.75), 7.59 (dd, 0.25H), 7.72-7.78 (m, 1H),7.81 (d, 0.75H), 7.95 (d, 0.25H).

The following compounds were obtained analogously to Synthesis Example26A:

Example Name/Structure/Starting materials Analytical data 27A tert-butyl(2E/Z)-3-(4-chloro-3-nitrophenyl)- 3-(1-fluorocyclopropyl)acrylate  

  from (4-chloro-3-nitrophenyl)(1-fluorocyclopropyl)- mathanone andtert-butyl (diethoxyphosphoryl)- acetate MS (DCI): m/z = 359 (M + NH₄)⁺.¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 1.01-1.10 (m, 2H), 1.19 (s,7.74H), 1.31-1.41 (m, 2H), 1.51 (s, 1.26H), 6.13 (s, 0.86H), 6.77 (s,0.14H), 7.55 (dd, 1H), 7.81 (d, 0.86H), 7.84 (d, 0.14H), 7.95 (d,0.86H), 8.29 (d, 0.14H). 28A ethyl (2E/Z)-3-(4-chloro-3-nitrophenyl)-3-cyclopropyl-2-methylacrylate  

  from (4-chloro-3-nitrophenyl)(cyclopropyl)- methanone and ethyl2-(diethoxyphosphoryl)- propanoate MS (DCI): m/z = 327 (M + NH₄)⁺. LC-MS(Method 7): R_(t) = 1.26 min; m/z = 310 (M + H)⁺.

Example 29A tert-Butyl3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate

200 mg (0.62 mmol) of tert-butyl(2E/Z)-3-(4-chloro-3-nitrophenyl)-3-cyclopropylacrylate were dissolvedin 12 ml of ethyl acetate, and 20 mug (0.06 mmol) of platinum (10% oncarbon) were added. The reaction mixture was stirred at RT under anatmosphere of hydrogen at atmospheric pressure for 12 hours. Thereaction mixture was then filtered off with suction through kieselguhr,and the filtrate was concentrated. The crude product was purified bychromatography on silica gel (mobile phase cyclohexane/ethyl acetate40:1). This gave 96 mg (52.1% of theory) of the target compound.

LC-MS (Method 5): R_(t)=1.24 min; m/z=296 (M+H)⁺.

Example 30A and Example 31A tert-Butyl3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate (enantiomers 1 and 2)

By preparative HPLC on a chiral phase, 500 mg (1.69 mmol) of theracemate of tert-butyl3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate (Example 29A) wereseparated into the enantiomers [column: Daicel Chiralpak AZ-H, 5 μm, 250mm×20 mm; mobile phase: iso-hexane/ethanol 90:10 (v/v); flow rate: 15ml/min; UV detection: 220 nm; temperature: 30° C.]:

Example 30A (Enantiomer 1)

Yield: 237 mg

R_(t)=4.91 min; chemical purity >99%; >99% ee

[Column: Daicel AZ-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/ethanol 90:10 (v/v); flow rate: 1 ml/min UV detection: 220 nm;temperature: 30° C.].

LC-MS (Method 5): R_(t)=123 min m/z=296 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.02-0.10 (m, 1H), 0.16-0.25 (m, 1H),0.27-0.36 (m, 1H), 0.45-0.54 (m, 1H), 0.85-0.98 (m, 1H), 1.28 (s, 9H),2.02-2.11 (m, 1H), 2.43-2.62 (m, 2H, partially obscured by DMSO signal),0.21 (br. s, 2H), 6.43 (dd, 1H), 6.64 (d, 1H), 7.06 (d, 1H).

[α]_(D) ²⁰=−22.3, c=0.465, Methanol.

Example 31A (Enantiomer 2)

Yield: 207 mg

R_(t)=5.25 min; chemical purity >99%; >99% ee

[Column: Daicel AZ-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/ethanol 90:10 (v/v); flow rate: 1 ml/min; UV detection: 220nm; temperature: 30° C.].

LC-MS (Method 5): R_(t)=1.23 in; m/z=296 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.02-0.10 (m, 1H), 0.16-0.25 (m, 1H),0.27-0.36 (m, 1H), 0.45-0.54 (m, 1H), 0.85-0.98 (m, 1H), 1.28 (s, 9H),2.02-2.11 (m, 1H), 2.43-2.62 (m, 2H, partially obscured by DMSO signal),5.21 (br. s, 2H), 6.43 (dd, 1H), 6.64 (d, 1H), 7.06 (d, 1H).

[α]_(D) ²⁰+24.1°, c=0.330, methanol.

Example 32A tert-Butyl3-(3-amino-4-chlorophenyl)-3-(1-fluorocyclopropyl)propanoate

384 mg (1.12 mmol) of ert-butyl(2E/Z)-3-(4-chloro-3-nitrophenyl)-3-(1-fluorocyclopropyl)-acrylate weredissolved in 12 ml of ethyl acetate, and 38 mg (0.17 mmol) of platinum(IV) oxide were added. The reaction mixture was stirred at RT under anatmosphere of hydrogen at atmospheric pressure overnight. The reactionmixture was then filtered off with suction through kieselguhr and thefiltrate was concentrated. The product was isolated from the residue bypreparative RP-HPLC (mobile phase methanol/water). This gave 68 mg (19%of theory) of the target compound.

LC-MS (Method 7): R_(t)=1.24 min; m/z=314 (M+H)⁺.

Example 33A (+/−)-tert-Butyl3-(3-amino-4-chlorophenyl)-3-cyclobutylpropanoate

Method A:

133 mg (9.432 mmol) of tert-butyl3-(3-amino-4-chlorophenyl)-3-cylobutylidenepropanoate were dissolved in20 ml of ethyl acetate. The solution was deoxygenated with argon, and 30mg of 10% palladium on carbon were added. At RT, the reaction mixturewas stirred under an atmosphere of hydrogen at atmospheric pressureovernight. The mixture was then filtered off through Celite, and thefiltrate was concentrated under reduced pressure. The product wasisolated from the residue by preparative RP-HPLC (mobile phaseacetonitrile/water), This gave 67 mg of the target compound (50% oftheory).

LC-MS (Method 5): R_(t)=1.31 min; m/z=310 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.24 (s, 9H), 1.47-1.57 (m, 1H),1.57-1.77 (m, 4H), 1.94-2.05 (m, 1H), 2.19 (dd, 1H) 2.31-2.40 (m, 1H),2.43 (dd, 1H), 2.71 (td, 1H), 5.13-5.22 (m, 2H), 6.36 (dd, 1H), 6.59 (d,1H), 7.04 (d, 1H).

Method B:

At RT, a solution of 189 mg (0.614 mmol) of tert-butyl3-(3-amino-4-chlorophenyl)-3-cyclobutylacrylate in 0.9 ml of methanolwas added to 39 mg (1.60 mmol) of magnesium turnings and a few grains ofiodine. The dark reaction mixture was stirred at RT overnight and thenadded to water and extracted with ethyl acetate. The organic phase waswashed with saturated sodium bicarbonate solution and saturated sodiumchloride solution, dried over magnesium sulphate and concentrated underreduced pressure. The product was isolated from the residue bypreparative RP-HPLC. This gave 57.7 mg of the target compound (30.3% oftheory).

Example 34A Ethyl(2E/Z)-3-(3-amino-4-chlorophenyl)-3-cyclopropyl-2-methylacrylate

Under argon, 2.53 g (8.17 mmol) of ethyl(2E/Z)-3-(4-chloro-3-nitrophenyl)-3-cyclopropyl-2-methylacrylate weredissolved in 10 ml of dioxane, and 9.22 g (40.84 mmol) of tin (II)chloride dihydrate were added. The reaction mixture was then heated to70° C. and stirred at this temperature overnight. After cooling to roomtemperature, about 20 ml of ethyl acetate were added and the reactionmixture was then added to about 20 ml of a 10% strength aqueouspotassium fluoride solution. The resulting mixture was stirredvigorously for 10 min. The phases were separated, and the aqueous phasewas then extracted two more times with in each case 10 ml of ethylacetate. The combined organic phases were washed with about 50 ml of asaturated sodium chloride solution, dried over magnesium sulphate andconcentrated under reduced pressure. This gave 2.2 g (96% of theory) ofthe target compound which was used without further purification for thenext step.

LC-MS (Method 7): R_(t)=1.19 min; m/z=280/282 (M+H)⁺.

Example 35A Ethyl3-(3-amino-4-chlorophenyl)-3-cyclopropyl-2-methylpropanoate(diastereomer mixture)

Under argon and at RT, a solution of 2.2 g (7.86 mmol) of ethyl(2E/Z)-3-(3-amino-4-chlorophenyl)-3-cyclopropyl-2-methylacrylate in 20ml of methanol was added to 497 mg (20.45 mmol) of magnesium turningsand a few grains of iodine. The dark reaction mixture was stirred at RTovernight and then allowed to stand under argon for two days. Thereaction solution was then diluted with ethyl acetate, and 1 Mhydrochloric acid was added. The mixture was stirred for 5 min and thenadjusted to pH 8-9 using saturated sodium bicarbonate solution. Theorganic phase was separated off, and the aqueous phase was extracted twomore times with ethyl acetate. The combined organic phases were washedwith saturated sodium chloride solution, dried over magnesium sulphateand concentrated under reduced pressure. The crude product was purifiedby chromatography on silica gel (mobile phase cyclohexane/ethyl acetate100:1→50:1→20:1). This gave 1.38 g (62% of theory) of the targetcompound.

LC-MS (Method 5): R_(t)=1.13 min; m/z=282/284 (M+H)⁺.

Example 36A Dimethyl (3-methylbutan-2-ylidene)malonate

Under argon and at 0° C., 10 g (75.7 mmol) of dimethyl malonate in 20 mlof chloroform were slowly added dropwise to a solution of 16.6 ml (151.4mmol) of titanium tetrachloride in 60 ml of chloroform. After theaddition had ended, the reaction solution was stirred at 0° C. foranother 30 min. At 0° C., 6.52 g (75.7 mmol) of 3-methyl-2-butanone in20 ml of chloroform were then added dropwise. The reaction mixture wasslowly warmed to room temperature and stirred at this temperature for 4h. The reaction solution was then once more cooled to 0° C., and 30.6 ml(378.5 mmol) of pyridine in 20 ml of chloroform were added. After theaddition had ended, the solution was warmed to room temperature andstirred at this temperature overnight. The reaction solution was thenonce more cooled to 0° C., and 50 ml of water were added slowly. Theresulting phases were separated, and the aqueous phase was extracted twomore times with in each case about 50 ml of dichloromethane. Thecombined organic phases were washed with saturated sodium bicarbonatesolution and with saturated sodium chloride solution, dried overmagnesium sulphate and concentrated under reduced pressure. The crudeproduct was purified by chromatography on silica gel (mobile phasecyclohexane/ethyl acetate 20:1). This gave 9.4 g (62% of theory) of thetarget compound.

GC-MS (Method 1): R_(t)=3.57 min; m/z=185 (M−CH₃)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.00 (d, 6H), 1.92 (s, 3H), 2.86-2.98(m, 1H), 3.67 (s, 3H), 3.69 (s, 3H).

The following compounds were obtained analogously to Synthesis Example36A:

Example Name/Structure/Starting materials Analytical data 37A dimethyl(1-cyclobutylethylidene)malonate  

  from dimethyl malonate and 1-cyclobutylethanone MS (DCI): m/z = 213(M + H)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.64-1.77 (m, 1H),1.79-1.93 (m, 1H), 1.94-2.09 (m, 4H), 2.03 (s, 3H), 3.43-3.55 (m, 1H),3.66 (s, 3H), 3.68 (s, 3H). 38A dimethyl(1-cyclopropylethylidene)malonate  

  from dimethyl malonate and 1-cyclopropyl- ethanone GC-MS (Method 1):R_(t) = 4.36 min; m/z = 198 (M)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =0.83-0.89 (m, 4H), 1.62 (s, 3H), 2.10-2.20 (m, 1H), 3.67 (s, 3H), 3.70(s, 3H).

Example 39A Dimethyl [2-(4-chlorophenyl)-3-methylbutan-2-yl]malonate

Under argon, 6.2 g (26 mmol) of 1-chloro-4-iodobenzene were dissolved in50 ml of THF and cooled to −78° C. 24 ml (312 mmol) of a 1.3 M solutionof isopropylmagnesium chloride×lithium chloride in THE were then slowlyadded dropwise. The reaction solution was then slowly warmed to −40° C.and stirred at this temperature for 2 h. The reaction solution was thenwarmed to −10° C., and 495 mug (2.6 mmol) of copper(I) iodide we added.S g (24.97 mmol) of dimethyl (3-methylbutan-2-ylidene)malonate,dissolved in 30 ml of THF, were the slowly added dropwise to thereaction solution. The resulting reaction mixture was slowly warmed toroom temperature and stirred at this temperature for 1 h. The mixturewas then cooled to 0° C., and ice-cold 1 M hydrochloric acid (pH˜2) wasadded carefully. The phases were separated, the aqueous phase was thenextracted three more times with ethyl acetate and the combined organicphases were dried over magnesium sulphate, filtered and concentrated todryness. The resulting crude product was initially pre-purifiedchromatographically on silica gel (mobile phase cyclohexane/ethylacetate 20:1). The product was then re-purified by preparative RP-HPLC(mobile phase methanol/water). This gave 3.38 g (42% of theory) of thetarget compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.63-0.71 (m, 6H), 1.52 (s, 3H),2.11-2.24 (m, 1H), 3.43 (s, 3H), 3.63 (s, 3H), 4.31 (s, 1H), 7.29-7.38(m, 4H).

The following compounds were obtained analogously to Synthesis Example39A:

Example Name/Structure/Starting materials Analytical data 40A dimethyl[1-(4-chlorophenyl)-1-cyclobutyl- ethyl]malonate  

  from 1-chloro-4-iodobenzene and dimethyl(1-cyclobutylethylidene)malonate ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =1.34-1.49 (m, 3H), 1.53 (s, 3H), 1.55-1.65 (m, 2H), 1.66-1.76 (m, 1H),2.79-2.91 (m, 1H), 3.38 (s, 3H), 3.66 (s, 3H), 4.07 (s, 1H), 7.35 (q,4H). 41A dimethyl (1-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-1-cyclopropylethyl)malonate  

  from 2-chloro-5-iodo-N,N-bis(4-methoxybenzyl)- aniline and dimethyl(1-cyclopropylethylidene)- malonate LC-MS (Method 5): R_(t) = 1.53 min;m/z = 566/568 (M + H)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = −0.16-−0.07(m, 1H), 0.01-0.09 (m, 1H), 0.16-0.24 (m, 1H), 0.24-0.32 (m, 1H), 1.04(s, 3H), 1.35-1.44 (m, 1H), 3.46 (s, 3H), 3.50 (s, 3H), 3.69 (s, 6H),4.06 (s, 4H), 4.15 (s, 1H), 6.83 (d, 4H), 7.05 (dd, 1H), 7.10 (d, 1H),7.21 (d, 4H), 7.28 (d, 1H).

Example 42A Dimethyl[1-(3-amino-4-chlorophenyl)-1-cyclopropylethyl]malonate

627 mg (1.11 mmol) of dimethyl(1-{3-[bis(4-methoxybenzyl)amino]-4-chlorophenyl}-1-cyclopropylethyl)malonatewere taken up in 60 ml of dichloromethane and 15 ml of water. 533 mg(2.44 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) were thenadded, and the reaction mixture was stirred at room temperature for 2hours. The reaction mixture was then added to about 50 ml of saturatedaqueous sodium bicarbonate solution. The phases were separated, and theaqueous phase was extracted three more times with in each case about 10ml of dichloromethane. The combined organic phases were dried overmagnesium sulphate and concentrated under reduced pressure. The productwas isolated from the residue by preparative RP-HPLC (mobile phasemethanol/water). This gave 283 mg of the target product (78% of theory).

LC-MS (Method 5): R_(t)=1.03 min; m/z=326/328 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.11-0.18 (m, 21H), 0.31-0.39 (m,2H), 1.12 (s, 3H), 1.40-1.49 (m, 1H), 3.53 (s, 3H), 3.57 (s, 3H), 4.10(s, 1H), 5.20 (s, 2H), 6.61 (dd, 1H), 6.91 (d, 1H), 7.05 (d, 1H).

Example 43A Methyl 3-(4-chlorophenyl)-3,4-dimethylpentanoate

3.38 g (10.81 mmol) of dimethyl[2-(4-chlorophenyl)-3-methylbutan-2-yl]malonate, 0.92 g (21.61 mmol) oflithium chloride and 0.2 ml of water in 10 ml of DMSO were heated underreflux for 4 h. After cooling, about 50 ml of diethyl ether were addedto the reaction solution, and the phases were separated. The organicphase was washed twice with water, dried over magnesium sulphate andconcentrated under reduced pressure. The crude product was purified bychromatography on silica gel (mobile phase cyclohexane/ethyl acetate10:1), This gave 2.3 g (84% of theory) of the target compound.

GC-MS (Method 1): R_(t)=5.43 min; m/z=254 (M)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.54 (d, 3H), 0.83 (d, 3H), 1.33 (s,3H), 1.86-1.98 (m, 1H), 2.62 (d, 1H), 2.87 (d, 1H), 3.35 (s, 3H), 7.32(s, 4H).

The following compounds were obtained analogously to Synthesis Example43A:

Example Name/Structure/Starting material Analytical data 44A methyl3-(4-chlorophenyl)-3-cyclobutylbutanoate  

  from dimetyl [1-(4-chlorophenyl)-1-cyclobutyl- ethyl]malonate MS(DCI): m/z = 284 (M + NH₄)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.36(s, 3H), 1.46- 1.58 (m, 2H), 1.58-1.67 (m, 2H), 1.67-1.78 (m, 2H),2.45-2.55 (m, 1H), partially obscured by DMSO signal), 2.55-2.64 (m,1H), 2.81 (d, 1H), 3.41 (s, 3H), 7.28-7.35 (m, 4H). 45A methyl3-(3-amino-4-chlorophenyl)-3-cyclopropyl- butanoate  

  from dimethyl [1-(3-amino-4-chlorophenyl)- 1-cyclopropylethyl]malonateLC-MS (Method 7): R_(t) = 1.12 min; m/z = 268/270 (M + H)⁺.

Example 46A Methyl 3-(4-chloro-3-nitrophenyl)-3,4-dimethylpentanoate

2.3 g (9.03 mmol) of methyl 3-(4-chlorophenyl)-3,4-dimethylpentanoatewere dissolved in 50 ml of dichloromethane and cooled to 0° C. 1.44 g(10.8 mmol) of nitronium tetrafluoroborate were then added a little at atime. After the addition had ended, the reaction solution was initiallystirred at 0°-10° C. for 1 h. The mixture was then slowly warmed to roomtemperature and stirred at this temperature for another 2 h. Thereaction mixture was then added to about 50 ml of water, the phases wereseparated and the organic phase was dried over magnesium sulphate. Thesolution was concentrated by evaporation and the residue obtained wasthen purified by chromatography on silica gel (mobile phasecyclohexane/ethyl acetate 20:1). This gave 2.3 g (85% of theory) of thetarget compound.

MS (DCI): m/z=317 (M+NH₄)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.56 (d, 3H), 0.84 (d, 3H), 1.35 (s,3H), 1.89-2.02 (m, 1H), 2.66 (d, 1H), 3.02 (d, 1H), 3.39 (s, 3H),7.63-7.71 (m, 2H), 7.96 (s, 1H).

The following compound was obtained analogously to Synthesis Example46A:

Example Name/Structure/Starting material Analytical data 47A methyl3-(4-chloro-3-nitrophenyl)-3-cyclobutyl- butanoate  

  from methyl 3-(4-chlorophenyl)-3-cyclobutyl- butanoate GC-MS (Method6): R_(t) = 7.62 min; m/z = 329 (M + NH₄)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ[ppm] = 1.38 (s, 3H), 1.50- 1.58 (m, 2H), 1.58-1.70 (m, 2H), 1.70-1.81(m, 2H), 2.54 (d, 1H, partially obscured by DMSO signal), 2.57-2.66 (m,1H), 2.95 (d, 1H), 3.44 (s, 3H), 7.62-7.70 (m, 2H), 7.94 (d, 1H).

Example 48A Methyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylbutanoate

1.79 g (5.74 mmol) of methyl3-(4-chloro-3-nitrophenyl)-3-cyclobutylbutanoate were dissolved in 50 mlof ethyl acetate, and about 150 mg of 10% palladium on carbon wereadded. At RT, the reaction mixture was stirred vigorously under anatmosphere of hydrogen at atmospheric pressure overnight. The mixturewas then filtered through Celite, and the filtrate obtained wasevaporated to dryness. The crude product was purified by chromatographyon silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave1.36 g of the target product (84% of theory).

LC-MS (Method 7): R_(t)=1.22 min; m/z=282 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.31 (s, 3H), 1.45-1.67 (m, 4H),1.68-1.77 (m, 2H), 2.43 (d, 1H), 2.48-2.60 (m, 1H, partially obscured byDMSO signal), 2.66 (d, 1H), 3.43 (s, 3H), 5.16 (br. s, 2H), 6.47 (dd,1H), 6.73 (d, 1H), 7.04 (d, 1H).

The following compound was obtained analogously to Synthesis Example48A:

Example Name/Structure/Starting material Analytical data 49A methyl3-(3-amino-4-chlorophenyl)-3,4-dimethyl- pentanoate  

  from methyl 3-(4-chloro-3-nitrophenyl)- 3,4-dimethylpentanoate LC-MS(Method 5): R_(t) = 1.11 min; m/z = 270/272 (M + H)⁺. ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.56 (d, 3H), 0.83 (d, 3H), 1.28 (s, 3H), 1.80-1.92(m, 1H), 2.57 (d, 1H), 2.72 (d, 1H), 3.38 (s, 3H), 5.15 (br. s, 2H),6.48 (dd, 1H), 6.73 (d, 1H), 7.04 (d, 1H).

Example 50A and Example 51A Methyl3-(3-amino-4-chlorophenyl)-3,4-dimethylpentanoate (enantiomers 1 and 2)

1700 mg (6.30 mmol) of the racemate of methyl3-(3-amino-4-chlorophenyl)-3,4-dimethylpentanoate (Example 49A) wereseparated into the enantiomers by preparative HPLC on a chiral phase[column: Daicel Chiralpak AY-H, 5 μm, 250 mm×20 mm; mobile phase:isohexane/isopropanol 95:5 (v/v); flow rate: 20 ml/min; UV detection:230 n; temperature: 25° C.]. The material obtained in each case wasre-purified by chromatography on silica gel (mobile phasecyclohexane/ethyl acetate 10:1).

Example 50A (Enantiomer 1)

Yield: 588 mug

R_(t)=7.21 min; chemical purity >99%; >99% ee

[Column: Daicel AY-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/(isopropanol+0.2% diethylamine) 95:5 (v/v); flow rate: 1ml/min; UV detection 230 nm; temperature: 30° C.].

LC-MS (Method 5): R_(t)=1.15 min; m/z=270 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.56 (d, 3H), 0.83 (d, 3H), 1.28 (s,3H), 1.80-1.92 (m, 1H), 2.57 (d, 1H), 2.72 (d, 1H), 3.38 (s, 3H), 5.15(br. s, 2H), 6.48 (dd, 1H), 6.73 (d, 1H), 7.04 (d, 11H).

[α]_(D) ²⁰=−30°, c=0.275, methanol.

Example 51A (Enantiomer 2)

Yield: 499 mg

R_(t)=8.59 min; chemical purity >99%; >96.7% ee

[Column: Daicel AY-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/(isopropanol+0.2% diethylamine) 95:5 (v/v); flow rate: 1ml/min; UV detection: 230 nm; temperature: 30° C.].

LC-MS (Method 5): R_(t)=1.15 min; m/z=270 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.56 (d, 3H), 0.83 (d, 3H), 1.28 (s,3H), 1.80-1.92 (m, 1H), 2.57 (d, 1H), 2.72 (d, 1H), 3.38 (s, 3H), 5.15(br. s, 2H), 6.48 (dd, 1H), 6.73 (d, 1H), 7.04 (d, 11H).

[α]_(D) ²⁰=+29°, c=0.270, methanol.

Example 52A and Example 53A Methyl3-(3-amino-4-chlorophenyl)-3-cyclobutylbutanoate (enantiomers 1 and 2)

1075 mg (3.82 mmol) of the racemate of methyl3-(3-amino-4-chlorphenyl)-3-cyclobutylbutanoate (Example 48A) wereseparated into the enantiomers by preparative HPLC on a chiral phase[column: Daicel Chiralpak AY-H, 5 μm, 250 mm×20 mm; mobile phase:isohexane/ethanol 95:5 (v/v); flow rate: 15 ml/min; UV detection: 220nm; temperature: 25° C.]:

Example 52A (Enantiomer 1)

Yield: 472 mg

R_(t)=6.40 min; chemical purity >99%; >99% ee

[Column: Daicel AY-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/(ethanol+0.2% diethylamine) 95:5 (v/v); flow rate: 1 ml/min;UV detection: 220 nm temperature: 40° C.].

LC-MS (Method 5): R_(t)=1.15 min; m/z=282/284 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.31 (s, 3H), 1.45-1.67 (m, 4H),1.68-1.78 (m, 2H), 2.43 (d, 1H), 2.48-2.60 (m, 1H, partially obscured byDMSO signal), 2.66 (d, 1H), 3.43 (s, 3H), 5.16 (br. s, 2H), 6.47 (dd,1H), 6.73 (d, 1H), 7.04 (d, 1H).

[α]_(D) ²⁰=−2.3°, c=0.450, methanol.

Example 53A (Enantiomer 2)

Yield: 489 mg

R_(t)=7.85 min; chemical purity >99%; >99% ee

[Column: Daicel AY-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/(ethanol+0.2% diethylamine) 95:5 (v/v); flow rate: 1 ml/min;UV detection: 220 nm; temperature: 40° C.].

[α]_(D) ²⁰=+2.5°, c=0.330, methanol.

Example 54A 1-(4-Chlorophenyl)prop-2-en-1-one

60 g (295.5 mmol) of 3-chloro-1-(4-chlorophenyl)propan-1-one weredissolved in 900 ml of acetonitrile. With ice bath cooling, 41.2 ml(295.5 mmol) of triethylamine were then slowly added dropwise to thesolution (exothermal reaction). After the addition had ended, thereaction solution was stirred at room temperature for 4 h. About oneliter of water, one liter of ethyl acetate and about 250 ml of saturatedsodium chloride solution were then added to the reaction mixture. Thephases were separated, the organic phase was then dried over magnesiumsulphate and filtered and the filtrate was concentrated to dryness. Thecrude product obtained was purified by chromatography on silica gel(about 1.3 kg) (mobile phase cyclohexane/ethyl acetate 6:1). This gave45 g of the target product (91% of theory).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=6.02 (d, 1H), 6.36 (dd, 1H),7.34-7.44 (m, 11H), 7.63 (d, 1H), 8.03 (d, 2H).

Example 55A (4-Chlorophenyl)(2,2-difluorocyclopropyl)methanone

Under argon, 91 g (546 mmol) of 1-(4-chlorophenyl)prop-2-en-1-one, 2.293g (54.6 mmol) of sodium fluoride and 2.41 g (10.92 mmol) of2,6-di-tert-butyl 4-methylphenol were heated in a 3 liter three-neckedflask to 110° C. and stirred at this temperature for 5 min. At aninternal temperature of 110°-125° C., 183 ml (928.5 mmol) oftrimethylsilyl 2,2-difluoro-2-(fluorosulphonyl)acetate were then slowlyadded dropwise over a period of 30-35 min to the solution (careful:evolution of gas). After the addition and the evolution of gas hadended, the reaction solution was stirred for another 20 min. Aftercooling, the reaction mixture was taken up in several liters of ethylacetate and extracted with saturated aqueous sodium bicarbonatesolution. The phases were separated, the organic phase was then driedover magnesium sulphate and filtered and the filtrate was concentratedto dryness. The crude product obtained was purified by chromatography onsilica gel (about 2 kg) (mobile phase cyclohexane/ethyl acetate 10:1).This gave 63 g of the target product (53% of theory),

¹H-NMR (400 MHz, DMSO-do): δ [ppm]=2.04-2.14 (m, 1H), 2.21-2.31 (m, 1H),3.98-4.09 (m, 1H), 7.65-7.70 (m, 2H), 8.06-8.11 (m, 2H).

Example 56A Methyl(2Z)-3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)acrylate and methyl(2E)-3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)acrylate

2.2 g (60% in mineral oil, 55 mmol) of sodium hydride were stirred with20 ml of THF and then filtered off with suction, and the filtercake waswashed with 20 ml of THF. Under argon, the sodium hydride purified inthis manner was introduced into 200 ml of THF. The mixture was thencooled to 0° C., and 10.1 g (55 mmol) of methyl(diethoxyphosphoryl)acetate, dissolved in 10 ml of THF, were added.After warming to room temperature, the solution was stirred for another1 h. 5.15 g (19.73 mmol) of(4-chlorophenyl)(2,2-difluorocyclopropyl)methanone in 50 ml of THF werethen added dropwise. After the addition had ended, the solution washeated to reflux and stirred for 2 h. The solution was then cooled to 5°C., and the mixture was poured into 400 ml of ice-water. The phases wereseparated, and the aqueous phase was then extracted three more timeswith ten-butyl methyl ether. The combined organic phases were washedsuccessively with 1 M hydrochloric acid and saturated sodium chloridesolution, dried over sodium sulphate, filtered and concentrated todryness. The crude product obtained was purified by chromatography onsilica gel (mobile phase cyclohexane/ethyl acetate 20:1→8:1). The E/Zisomers were isolated in separated form. This gave 2.23 g (37% oftheory) of methyl(2E)-3-(4-chlorophenyl)-3-(2,2-difluoro-cyclopropyl)acrylate and 1.6 g(24.4% of theory) of methyl(2Z)-3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)acrylate.

Methyl (2E)-3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)acrylate

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.00-1.12 (m, 1H), 1.92-2.06 (m, 1H),3.21-3.37 (m, 1H, partially obscured by H₂O signal), 3.71 (s, 3H) 6.42(d, 1H), 7.49 (d, 2H), 7.55 (d, 2H).

Methyl (2Z)-3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)acrylate

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.83-1.96 (m, 1H), 1.97-2.09 (m, 1H),2.76-2.88 (m, 1H) 3.51 (s, 3H), 6.10 (s, 1H), 7.23 (d, 2H), 7.46 (d,2H).

Example 7A Methyl3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)propanoate and methyl3-(4-chlorophenyl)-5,5-difluorohexanoate

1000 mg (3.67 mmol) of methyl(2Z)-3-(4-chlorphenyl)-3-(22-difluorocyclopropyl)acrylate were dissolvedin 75 ml of ethyl acetate and hydrogenated in a continuous-flowhydrogenation apparatus (H-Cube, from Thales Nano, Budapest) fitted witha catalyst cartridge (10% palladium on carbon) at a flow rate of 1ml/min and at room temperature and atmospheric pressure using hydrogen.After the reaction had gone to completion, the reaction mixture wasconcentrated under reduced pressure. This gave 980 mg of a productmixture consisting of methyl3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)propanoate and methyl3-(4-chlorphenyl)-5,5-difluorohexanoate as a colourless oil.

GC-MS (Method 6): R_(t)=5.38 min; m/z=292/2941296 (M+NH₄)⁺.

Example 58A Methyl3-(4-chloro-3-nitrophenyl)-3-(2,2-difluorocyclopropyl)propanoate andmethyl 3-(4-chloro-3-nitrophenyl)-5,5-difluorohexanoate

610 mg of the mixture consisting of methyl3-(4-chlorophenyl)-3-(2,2-difluorocyclopropyl)-propanoate and methyl3-(4-chlorophenyl)-5,5-difluorohexanoate (Example 57A) were dissolved in12 ml of dichloromethane and cooled to 0° C. 351 mg (2.65 mmol) ofnitroniumtetrafluoroborate were then added a little at a time. After theaddition had ended, the reaction solution was stirred at 0°-11° C. for 1h. The mixture was then slowly warmed to room temperature and stirred atthis temperature for a further 2 h. The reaction mixture was then addedto about 20 ml of water, the phases were separated and the organic phasewas dried over magnesium sulphate. The solution was concentrated byevaporation and the residue obtained was then purified by chromatographyon silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave637 mg of the mixture of the two target compounds.

GC-MS (Method 6): R_(t)=6.74 min; m/z=337/339/341 (M+NH₄)⁺.

Example 59A Methyl3-(3-amino-4-chlorophenyl)-3-(2,2-difluorocyclopropyl)propanoate andmethyl 3-(3-amino-4-chlorophenyl)-5,5-diflourohexanoate

640 mg of the mixture consisting of methyl3-(4-chloro-3-nitrophenyl)-3-(2,2-difluorocyclopropyl)propenoate andmethyl 3-(4-chloro-3-nitrophenyl)-5,5-difluorohexanoate (Example 58A)were dissolved in 40 ml of ethyl acetate, and 106 mg of palladium oncarbon (10%) were added. The reaction mixture was stirred vigorouslyunder an atmosphere of hydrogen at atmospheric pressure overnight. Themixture was than filtered through Celite, and the filtrate obtained wasevaporated to dryness. The crude product was purified by chromatographyon silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave361 mg of the mixture of the two target compounds.

LC-MS (Method 5): R_(t)=0.98 min; m/z=290/292 (M+H)⁺.

Example 60A (+)-Ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate

At room temperature, 133 ml (1.82 mol) of thionyl chloride were addedslowly to 287 g (1.65 mol) of (3R)-4,4,4-trifluoro-3-methylbutanoic acid[A. Gerlach and U. Schulz, Specialty Chemicals Magazine 24 (4), 37-38(2004); CAS Acc.-No. 142:179196] in 580 ml of ethanol. The reactionsolution was then heated to 80° C. and stirred at this temperature for 2h. The mixture was then cooled to room temperature, 250 ml of water wereadded slowly and the mixture was extracted three times with in each case150 ml of tert-butyl methyl ether. The combined organic phases weredried over sodium sulphate. After filtration the solvent was removedunder reduced pressure at 30° C. and a pressure of 300 mbar. The crudeproduct was then distilled at 100 mbar and a head temperature of 65° C.This gave 225.8 g (113 mol, 74% of theory) of the title compound as acolourless liquid.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 4.10 (2H, q), 2.88-2.72 (1H, m),2.66-2.57 (1H, m), 2.46-2.36 (1H, m), 1.19 (3H, t), 1.11 (3H, d).

GC-MS (Method 1): R_(t)=1.19 min; m/z=184 (M)⁺.

[α]_(D) ²⁰=+16.1°, c=0.41, methanol.

Example 61A Ethyl 4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate(diastereomer mixture)

Under argon 196.9 mg (0.88 mmol) of palladium(II) acetate and 724.8 mg(1.84 mmol) of 2-dicyclohexylphosphino-2′-(N-dimethylamino)biphenyl wereinitially charged in 50 ml of anhydrous toluene. 43.8 ml (43.8 mmol) ofa 1 M solution of lithium hexamethyldisilazide in THF were added slowly,and the reaction solution was then stirred at RT for 10 min. Thereaction solution was then cooled to −10° C., 7 g (38.0 mmol) of(+/−)-ethyl 4,4,4-trifluoro-3-methylbutanoate were added slowly and themixture was stirred at −10° C. for 10 min. 5 g (29.2 mmol) of4-bromotoluene, dissolved in 50 ml of toluene, were then added dropwise,and the reaction solution was warmed first to RT and then heated to 80°C. The mixture was stirred at this temperature for 2 h and then cooledto RT and stirred overnight. After the reaction had ended (monitored byTLC; mobile phase cyclohexane/dichloromethane 2:1), the reaction mixturewas filtered through kieselguhr, the residue was washed repeatedly withethyl acetate and dichloromethane and the combined filtrates wereconcentrated under reduced pressure. The crude product obtained waspurified chromatographically on silica gel (mobile phase petroleumether/dichloromethane 4:1→3:1). This gave 3.91 g (14.3 mmol, 48.8% oftheory) of the title compound as a colourless liquid.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.26 (2H, d), 7.20-7.12 (2H, m),4.17-3.95 (2H, m), 3.74 (0.25H, d), 3.66 (0.75H, d), 3.35-3.07 (1H, m),2.29 (2.25H, s), 2.28 (0.75H, s), 1.17 (0.75H, d), 1.11 (3H, t), 0.76(2.25H, d).

GC-MS (Method 1): R_(t)=4.20 min, m/z=275 (M+H)⁺ (diastereomer 1);R_(t)=4.23 min, m/z=275 (M+H)⁺ (diastereomer 2).

Example 62A Ethyl(3R)-4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate (diastereomermixture)

Preparation of solution A: Under argon, 16.3 ml of a 1 M solution oflithium hexamethyldisilazide in toluene were cooled to −10° C. to −20°C. (cooling with acetone/dry ice), and 2 g (10.86 mmol) of (+)-ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate, dissolved in 10 ml of toluene,were added slowly; during the addition, it was made sure that atemperature of −10° C. was not exceeded. The solution was then stirredfor another 10 min at at most −10° C.

Preparation of solution B: Under argon, 2.415 g (14.12 mmol) of4-bromotoluene were dissolved at RT in 10 ml of toluene, and 73 mg (0.33mmol) of palladium(II) acetate and 269 mg (0.68 mmol) of2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl were added. Thesolution was stirred at RT for 10 min.

First, the cooling both was removed from solution A. Solution B was thenslowly added dropwise to solution A, which was still cold. The combinedsolutions were then slowly warmed to RT and stirred at this temperaturefor 1 h. The reaction solution was then heated to 80° C. (internaltemperature) and stirred at this temperature for 3 h. The reactionsolution was then slowly cooled to RT and stirred for another 12 h.Finally, the reaction mixture was filtered through kieselguhr, theresidue was washed repeatedly with toluene and the combined filtrateswere concentrated under reduced pressure. The crude product obtained waspurified chromatographically on silica gel (mobile phasecyclohexane/dichloromethane 10:1→4:1). This gave 2.35 g (79% of theory)of the title compound.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 0.76 (d, 2.13H), 1.11 (t, 3H), 1.17(d, 0.87H), 3.07-3.30 (m, 1H), 3.66 (d, 0.7H), 3.75 (d, 0.3H), 3.94-4.15(n, 2H), 7.12-7.20 (m, 2H), 7.23-7.29 (m, 2H).

GC-MS (Method 1): R_(t)=3.88 min, m/z=275 (M+H)⁺ (diastereomer 1);R_(t)=3.90 min, m/z=275 (M+H)⁺ (diastereomer 2).

Example 63A Ethyl(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoate (diastereomermixture)

Preparation of solution A: Under argon, 163.9 ml of a 1 M solution oflithium hexamethyldisilazide in toluene were cooled to −10° C. to −20°C. (cooling using acetone/dry ice), and 20 g (108.6 mmol) of (+)-ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate, dissolved in 150 ml of toluene,were added slowly; during the addition care was taken that a temperatureof −10° C. was not exceeded. The solution was then stirred for another10 min at at most −10° C.

Preparation of solution B: Under argon, 27.03 g (141.2 mmol) of1-bromo-4-chlorobenzene were dissolved at RT in 100 ml of toluene, and731 mg (3.26 mmol) of palladium(II) acetate and 2.693 g (6.84 mmol) of2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl were added. Thesolution was stirred at RT for 10 min.

First, the cooling bath was removed from solution A. Solution B was thenslowly added dropwise to solution A, which was still cold. The combinedsolutions were then slowly warmed to RT and stirred at this temperaturefor 1 h. The reaction solution was then heated to 80° C. (internaltemperature) and stirred at this temperature for 3 h. The reactionsolution was then slowly cooled to RT and stirred for another 12 h. Thereaction mixture was finally filtered through kieselguhr, the residuewas washed repeatedly with toluene and the combined filtrates wereconcentrated under reduced pressure. The crude product obtained waspurified chromatographically on silica gel (mobile phasecyclohexane/dichloromethane 4:1). This gave 27.4 g (92.98 mmol, 86% oftheory) of the title compound as a yellow oil in a diastereomer ratio of3:1.

GC-MS (Method 1): R_(t)=4.45 min, m/z=294 (M)⁺ (diastereomer 1);R_(t)=4.48 min, m/z=294 (M)⁺ (diastereomer 2).

The following compounds were obtained analogously to Synthesis Examples61A and 63A:

Example Name/Structure/Starting materials Analytical data 64A ethyl(3R)-4,4,4-trifluoro-2-(4-isopropylphenyl)- 3-methylbutanoate  

  from 1-bromo-4-isopropylbenzene and ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate GC-MS (Method 1): R_(t) = 4.61min, m/z = 302 (M)⁺ (diastereomer 1); R_(t) = 4.64 min, m/z = 302 (M)⁺(diastereomer 2). 65A ethyl (3R)-2-(4-tert-butylphenyl)-4,4,4-trifluoro-3-methylbutanoate  

  from 1-bromo-4-tert-butylbenzene and ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate GC-MS (Method 1): R_(t) = 4.83min, m/z = 317 (M + H)⁺ (diastereomer 1); R_(t) = 4.85 min, m/z = 317(M + H)⁺ (diastereomer 2). MS (DCI): m/z = 334 (M + NH₄)⁺. 66A ethyl(3R)-2-(4-chloro-3-methoxyphenyl)- 4,4,4-trifluoro-3-methylbutanoate  

  from 4-bromo-1-chloro-2-methoxybenzene and ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate GC-MS (Method 1): R_(t) = 5.34min, m/z = 324/326 (M)⁺. 67A ethyl2-(4-chloro-3-methylphenyl)-4,4,4-trifluoro- 3-methylbutanoate  

  from 4-bromo-1-chloro-2-methylbenzene and ethyl4,4,4-trifluoro-3-methylbutanoate GC-MS (Method 1): R_(t) = 4.81 min,m/z = 308/310 (M)⁺ (diastereomer 1); R_(t) = 4.84 min, m/z = 308/310(M)⁺ (diastereomer 2).

Example 68A Ethyl(3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoate (diastereomermixture)

24.4 ml (24.4 mmol) of a 1 M solution of lithium hexamethyldisilazide intoluene were cooled to −10° C., and a solution of 3.0 g (16.29 mmol) of(+)-ethyl (3R)-4,4,4-trifluoro-3-methylbutanoate in 15 ml of abs.toluene was added dropwise. The mixture was stirred for 10 min. At −10°C., a solution, prepared beforehand, of 3.92 g (21.18 mmol) of1-bromo-4-ethylbenzene, 110 mg (0.49 mmol) of palladium(II) acetate and404 mg (1.03 mmol) of2′-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl in 20 ml of abs.toluene was then added dropwise. The resulting reaction mixture was thenstirred first at RT for 1 h and then at 80° C. for 3 h. The mixture wasthen concentrated under reduced pressure and the residue was taken up inethyl acetate and added to water. The aqueous phase was re-extractedwith ethyl acetate, and the combined organic phases were washed withsaturated ammonium chloride solution and saturated sodium chloridesolution, dried over magnesium sulphate and concentrated under reducedpressure. The residue gave, after chromatography on silica gel (mobilephase first cyclohexane, then gradient cyclohexane/ethyl acetate200:1→50:1), 3.051 g of the title compound (64.9% of theory,diastereomer ratio about 3:1).

LC-MS (Method 4): R_(t)=1.52 mini, m/z=289 (M+H)⁺ (minor diastereomer);R_(t)=1.54 min, m/z=289 (M+H)⁺ (major diastereomer).

¹H-NMR (400 MHz, DMSO-d₆): major diastereomer: δ [ppm]=0.76 (d, 3H),1.13 (t, 3H), 1.17 (t, 3H), 2.55-2.63 (m, 2H), 3.21-3.31 (m, 1H), 3.67(d, 1H), 3.95-4.16 (m, 2H), 7.15-7.23 (m, 2H), 7.25-7.31 (m, 2H).

The following compounds were prepared in a similar manner from (+)-ethyl(3R)-4,4,4-trifluoro-3-methylbutanoate and the appropriate phenylbromides:

Example 69A Ethyl(3R)-4,4,4-trifluoro-3-methyl-2-(4-vinylphenyl)butanoate (diastereomermixture)

GC-MS (Method 1): R_(t)=4.64 min and 4.66 min; in each case m/z=286(M)⁺.

¹H-NMR (400 MHz, DMSO-d₆): major diastereomer. δ [ppm]=0.79 (d, 3H),1.12 (t, 3H), 3.22-3.32 (m, 1H), 3.73 (d, 1H), 3.99-4.17 (m, 2H), 5.28(d, 11H), 5.84 (d, 1H), 6.72 (dd, 1H), 7.34-7.40 (m, 2H), 7.45-7.51 (m,2H).

Example 70A Ethyl(3R)-4,4,4-trifluoro-2-(4-fluorophenyl)-3-methylbutanoate (diastereomermixture)

GC-MS (Method 1): R_(t)=3.63 min, m/z=278 (M)⁺ (minor diastereomer);R_(t)=3.6 min, m/z=278 (M)⁺ (major diastereomer).

¹H-NMR (400 MHz, DMSO-d₆): major diastereomer. δ [ppm]=0.77 (d, 3H),1.12 (t, 3H), 3.23-3.30 (m, 1H), 3.79 (d, 1H), 4.01-4.14 (m, 2H),7.19-7.24 (m, 2H), 7.43-7.47 (m, 2H).

Example 71A Ethyl(3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoate(diastereomer mixture)

GC-MS (Method 1): R_(t)=4.33 min and 4.36 min; in each case m/z=312(M)⁺.

¹H-NMR (400 MHz, DMSO-d₆): major diastereomer. δ [ppm]=0.80 (d, 3H),1.08-1.19 (m, 3H), 3.34-3.41 (m, 1H), 3.88 (d, 1H), 4.01-4.18 (m, 2H),7.28-7.34 (m, 1H), 7.51-7.64 (m, 2H).

Example 72A Ethyl(3R)-2-[4-(2,2-difluorocyclopropyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate

1.58 g (5.52 mmol) of ethyl(3R)-4,4,4-trifluoro-3-methyl-2-(4-vinylphenyl)butanoate, 23 mg (0.55mmol) of sodium fluoride and 24 mg (0.11 mmol) of 2,6-di-tert-buy4-methylphenol were heated to 110° C. and stirred for 5 minutes. 1.9 ml(9.38 mmol) of trimethylsilyl 2,2-difluoro-2-(fluorosulphonyl)acetatewere then slowly added dropwise, and the mixture was stirred at 110° C.for 60 min (careful: evolution of gas after about 30 min). After coolingto room temperature and addition of ethyl acetate and saturated aqueoussodium bicarbonate solution, the organic phase was separated off driedover magnesium sulphate, filtered and concentrated to dryness. The crudeproduct was purified chromatographically on silica gel (mobile phasecyclohexane/-dichloromethane 4:1). This gave 1.5 g of the title compound(81% of theory).

GC-MS (Method 1): R_(t)=4.99 min, m/z=336 (M)⁺ (diastereomer 1);R_(t)=5.01 min, m/z=336 (M)⁺ (diastereomer 2).

MS (DCI): m/z=354 (M+NH₄)⁺.

Example 73A Ethyl2-[4-(bromomethyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate

2.25 g (8.2 mmol) of ethyl4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate, 1.53 g (8.6 mmol)of N-bromosuccinimide and 67 mg (0.41 mmol) of2,2′-azobis-2-methylpropanenitrile) in 36 ml of trichloromethane werestirred under reflux overnight. After the reaction had gone tocompletion, the succinimide was filtered off, the filter residue waswashed with dichloromethane and the filtrate was concentrated underreduced pressure. The crude product was purified chromatographically onsilica gel (mobile phase cyclohexan/ethyl acetate 40:1). This gave 2.667g (7.5 mmol, 92% of theory) of a yellowish oil.

GC-MS (Method 1): R_(t)=5.72 min, m/z=373 (M−Br)⁺ (diastereomer 1);R_(t)=5.74 min, m/z=373 (M−Br)⁺ (diastereomer 2).

Example 74A Ethyl4,4,4-trifluoro-3-ethyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoate

529 mg (2.78 mmol) of copper(I) iodide and 4 g (20.82 mmol) of methyl2,2-difluoro-2-(fluorosulphonyl)acetate were added to 3.77 g (10.67mmol) of ethyl2-[4-(bromo-methyl)phenyl]-4,4,4-trifluo-3-methylbutanoate in 40 ml of1-methylpyrrolidin-2-one, and the mixture was stirred at 80° C.overnight. After the reaction had ended, the reaction solution wasslowly poured into 100 ml of ice-water. The mixture obtained was thenextracted three times with diethyl ether. The combined organic phaseswere dried over magnesium sulphate. After filtration, the solvent wasremoved under reduced pressure. The crude product obtained was purifiedchromatographically on silica gel (mobile phasecyclohexane/dichloromethane 4:1). This gave 1.48 g (4.32 mmol, 41% oftheory) of the title compound as a yellowish oil.

GC-MS (Method 1): R_(t)=4.06 min, m/z=342 (M)⁺ (diastereomer 1);R_(t)=4.09 min, m/z=342 (M)⁺ (diastereomer 2).

MS (DCI): m/z=360 (M+NH₄)⁺.

Example 75A Methyl (4-chlorophenyl)(3-oxocyclopentyl)acetate

Under argon, 14.8 ml (105.6 mmol) of diisopropylamine were initiallycharged in 150 ml of THF, the mixture was cooled to −30° C. and 42.3 ml(105.75 mmol) of a 2.5 M solution of n-butyllithium in hexane were addedslowly. The reaction solution was then warmed to −20° C., 15 g (81.25mmol) of methyl (4-chlorophenyl)acetate, dissolved in 90 ml of THF, wereadded slowly and the mixture was stirred at this temperature for 2 h.The reaction solution then cooled to −78° C., and 7.2 ml (86.1 mmol) of2-cyclopenten-1-one, dissolved in 60 ml of THF, were added slowly. Afterthe addition had ended, the solution was stirred at −78° C. for anotherhour. After TLC (mobile phase cyclohexane/ethyl acetate 9:1), saturatedaqueous ammonium chloride solution was added and the product was takenup in ethyl acetate. The aqueous phase was extracted twice with ethylacetate. The combined organic phases were dried over magnesium sulphate.After filtration, the solvent was removed under reduced pressure. Thecrude product was purified chromatographically on silica gel (mobilephase cyclohexane/ethyl acetate 4:1). This gave 15.65 g (58.67 mmol, 72%of theory) of the title compound as a yellowish oil.

GC-MS (Method 1): R_(t)=7.02 min, m/z=266 (M)⁺ (diastereomer 1);R_(t)=7.04 min, m/z=266 (M)⁺ (diastereomer 2).

MS (DCI): m/z=284 (M+NH)⁺.

Example 76A Methyl (4-chlorophenyl)(3,3-difluorocyclopentyl)acetate

Under argon, 82.5 ml (82.14 mmol) of a 50% strength solution of1,1′-[(trifluoro-λ⁴-sulphanyl)-imino]bis(2-methoxyethane) (Desoxofluor)in THF, diluted with 200 ml of toluene, were initially charged andcooled to 5° C., and 744 μl (5.87 mmol) of a 1 M solution of borontrifluoride/diethyl ether complex were added slowly. The mixture wasstirred at 5° C. for 2 h. 15.65 g (58.67 mmol) of methyl(4-chlorophenyl)(3-oxocyclopentyl)acetate, dissolved in 200 ml oftoluene, were then added slowly, and the reaction solution wassubsequently warmed to 55° C. and stirred at this temperature for 60 h.The reaction mixture was then added to a mixture, cooled to 0° C.,consisting 3 of 100 ml of toluene and 100 ml of 2 M aqueous sodiumhydroxide solution. The organic phase was separated off, and the aqueousphase was extracted three more times with ethyl acetate. The combinedorganic phases were dried over sodium sulphate. After filtration, thesolvent was removed under reduced pressure. The crude product waspurified chromatographically on silica gel (mobile phasecyclohexane/ethyl acetate 7:1). This gave 13.24 g (45.86 mmol, 78% oftheory) of the title compound as a colourless oil.

MS (DCI): m/z=306 (M+NH₄)⁺.

GC-MS (Method 1): R_(t)=5.83 min, m/z=288 (M)⁺ (diastereomer 1);R_(t)=5.86 min, m/z=288 (M)⁺ (diastereomer 2).

Example 7A(+)-(2S,3R)-2-(4-Chlorphenyl)-4,4,4-trifluoro-3-methylbutanoic acid

Method A:

5.086 g (17.26 mmol) of ethyl(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoate were dissolvedin 68 ml of dioxane, and 34 ml of 1 N aqueous sodium hydroxide solutionwere added. The reaction was stirred at 50° C. for 2 h. The reactionmixture was then acidified with 1 N hydrochloric acid to pH 1 andrepeatedly extracted with dichloromethane. The combined organic phaseswere washed with saturated sodium chloride solution, dried over sodiumsulphate and concentrated under reduced pressure. This gave 3.9 g (14.63mmol, 85% of theory, 83% de) of the target compound.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.95-12.73 (1H, br. s), 7.49-7.34(1H, m), 3.68 (1H, d), 3.31-3.18 (1H, m), 1.20 (0.251H, d), 0.78(2.751H, d).

GC-MS (Method 1): R_(t)=4.85 min; m/z=266 (M)⁺.

[α]_(D) ²⁰=+57.2°, c=0.41, methanol.

Method B:

16.28 g (55.24 mmol) of ethyl(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoate were dissolvedin 220 ml of dioxane, and 110.5 ml of 1 N aqueous sodium hydroxidesolution were added. The reaction was stirred at 50° C. for 3 h. Thedioxane was then removed on a rotary evaporator, and the aqueoussolution that remained was, with ice-cooling, neutralized with 1 Nhydrochloric acid (˜pH 7). The precipitated solid was filtered off withsuction and dried under high vacuum at 40° C. overnight. This gave 9.2 gof the target compound as a slightly beige solid (fraction 1; 62.5% oftheory, 94% de). The filtrate was acidified by further addition of 1 Nhydrochloric acid (˜pH 1) and stirred overnight. Once more, theprecipitated solid was filtered off with suction and dried under highvacuum at 40° C. overnight. This gave a further 3.46 g of the targetcompound as a white solid (fraction 2; contaminated with 10% of thesecond diastereomer). The aqueous filtrate that remained was repeatedlyextracted with dichloromethane, and the combined organic phases weredried over magnesium sulphate and concentrated under reduced pressure.This gave another 2.44 g of the target compound as a colourless oil(fraction 3; contaminated with 15% of the second diastereomer).Fractions 2 and 3 were finally combined and re-purifiedchromatographically on silica gel (mobile phase cyclohexane/ethylacetate 10:1). This gave 3.7 g of the target compound as a white solid(fraction 4; 25% of theory, >95% de).

Fraction 1 (=sodium salt of the title compound):

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.44-7.33 (41, m), 3.61 (1H, d),3.30-3.15 (1H, m), 1.17 (0.09H, d, minor diastereomer), 0.76 (2.91H, d,major diastereomer).

Fraction 4:

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 13.03-12.69 (br. s, 1H), 7.47-7.39(4H, m), 3.68 (1H, d), 3.39-3.17 (1H, m, partially obscured by H₂Osignal), 0.77 (3H, d).

Compounds listed in the table below were prepared in an analogousmanner.

Example Name/Structure/Starting material Analytical data 78A(2S,3R)-4,4,4-trifluoro-3-methyl-2-(4-methyl- phenyl)butanoic acid  

  from ethyl (3R)-4,4,4-trifluoro-3-methyl- 2-(4-methylphenyl)butanoateGC-MS (Method 1): R_(t) = 4.17 min; m/z = 246 (M)⁺. ¹H-NMR (400 MHz,DMSO-d₆, δ/ppm): 0.75 (d, 2.75H, major diastereomer), 1.19 (d, 0.25H,minor diastereomer), 2.29 (s, 3H), 3.15-3.28 (m, 1H), 3.55 (d, 0.915H,major diastereomer), 3.60 (d, 0.085H, minor diastereomer), 7.17 (d, 2H),7.24 (d, 2H), 12.68 (br. s. 1H) (83% de). 79A(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro- 3-methylbutanoic acid  

  from ethyl (3R)-2-(4-ethylphenyl)-4,4,4-trifluoro- 3-methylbutanoateLC-MS (Method 5): R_(t) = 1.06 min; m/z = 259 (M − H)⁻. ¹H-NMR (400 MHz,DMSO-d₆, δ/ppm): 0.75 (d, 3H), 1.17 (t, 3H), 2.59 (q, 2H), 3.14-3.29 (m,1H), 3.56 (d, 1H), 7.20 (d, 2H), 7.27 (d, 2H), 12.53-12.86 (br. s, 1H).80A (2S,3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid  

  from ethyl (3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoate LC-MS (Method 5): R_(t) = 1.06 min;m/z = 259 (M − H)⁻. ¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 0.80 (d, 2.75H,major diastereomer), 1.19 (d, 0.25H, minor diastereomer), 3.21-3.37 (m,1H, partially obscured by H₂O signal), 3.75 (d, 1H), 7.29 (dd, 1H), 7.51(dd, 1H), 7.60 (t, 1H), 12.97 (br. s, 1H) (83% de). 81A(2S,3R)-4,4,4-trifluoro-2-(4-fluorophenyl)- 3-methylbutanoic acid  

  from ethyl (3R)-4,4,4-trifluoro- 2-(4-fluorophenyl)-3-methylbutanoateLC-MS (Method 5): R_(t) = 0.97 min; m/z = 249 (M − H)⁻. ¹H-NMR (fromsodium salt; 400 MHz, DMSO-d₆, δ/ppm): 0.76 (d, 2.73H, majordiastereomer), 1.19 (d, 0.27H, minor diastereomer), 3.16-3.31 (m, 1H),3.66 (d, 1H), 7.15-7.23 (m, 2H), 7.37-7.46 (m, 2H) (82% de). 82A(2S,3R)-4,4,4-trifluoro-2-(4-isopropylphenyl)- 3-methylbutanoic acid  

  from ethyl (3R)-4,4,4-trifluoro-2-(4-isopropylphenyl)-3-methylbutanoate ¹H-NMR (400 MHz, DMSO-d₆,δ/ppm): 12.56 (1H, br. s), 7.25 (4H, q), 3.56 (1H, d), 3.28-3.16 (1H,m), 2.94-2.81 (1H, m), 1.19 (6H, d), 0.75 (3H, d). GC-MS (Method 1):R_(t) = 4.93 min; m/z = 274 (M)⁺. 83A(2S,3R)-2-(4-tert-butylphenyl)-4,4,4-trifluoro- 3-methylbutanoic acid  

  from ethyl (2S,3R)-2-(4-tert-butylphenyl)-4,4,4-trifluoro-3-methylbutanoate GC-MS (Method 1): R_(t) = 5.15 min;m/z = 288 (M)⁺. 84A 4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoro-ethyl)phenyl]butanoic acid  

  from ethyl 4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoate ¹H-NMR (400 MHz, DMSO-d₆,δ/ppm): 12.95-12.59 (1H, br. s), 7.37 (4H, q), 3.70-3.57 (3H, m),3.30-3.18 (1H, m), 0.76 (3H, d). GC-MS (Method 1): R_(t) = 4.45 min; m/z= 315 (M + H)⁺. 85A (4-chlorophenyl)(3,3-difluorocyclopentyl)acetic acid 

  from methyl (4-chlorophenyl)(3,3-difluoro- cyclopentyl)acetate ¹H-NMR(400 MHz, DMSO-d₆, δ/ppm): 12.59 (1H, br. s), 7.38 (4H, q), 3.51 (0.5H,d), 3.48 (0.5H, d), 2.77-2.60 (1H, m), 2.42- 2.27 (0.5H, m), 2.26-1.20(5.5H, m). GC-MS (Method 1): R_(t) = 6.33 min, m/z = 274 (M)⁺(diastereomer 1); R_(t) = 6.38 min, m/z = 274 (M)⁺ (diastereomer 2). 86A(2S,3R)-2-(4-chloro-3-methoxyphenyl)- 4,4,4-trifluoro-3-methylbutanoicacid  

  from ethyl (3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-trifluoro-3-methylbutanoate ¹H-NMR (400 MHz, DMSO-d₆, δ/ppm):12.91-12.71 (1H, br. s), 7.41 (1H, d), 7.18 (1H, d), 6.98 (1H, dd), 3.86(3H, s), 3.66 (1H, d), 3.40-3.19 (1H, m), 0.79 (3H, d). LC-MS (Method2): R_(t) = 2.20 min; m/z = 295/297 (M − H)⁻. 87A2-(4-chloro-3-methylphenyl)-4,4,4-trifluoro- 3-methylbutanoic acid  

  from ethyl 2-(4-chloro-3-methylphenyl)-4,4,4-trifluoro-3-methylbutanoate GC-MS (Method 1): R_(t) = 5.20 min,m/z = 280/282 (M)⁺ (diastereomer 1); R_(t) = 5.23 min, m/z = 280/282(M)⁺ (diastereomer 2). 88A(2S,3R)-2-[4-(2,2-difluorocyclopropyl)phenyl]-4,4,4-trifluoro-3-methylbutanoic acid (diastereomer mixture)  

  (from ethyl (2S,3R)-2-[4-(2,2-difluorocyclo-propyl)phenyl]-4,4,4,-trifluoro- 3-methylbutanoate) LC-MS (Method 5):R_(t) = 1.09 min; m/z = 307 (M − H)⁻. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]= 0.76 (d, 3H), 1.86-2.04 (m, 2H), 2.92-3.06 (m, 1H), 3.18- 3.29 (m,1H), 3.61 (d, 1H), 7.27 (d, 2H), 7.34 (d, 2H), 12.72 (br. s, 1H).

Example 89A (3R)-2-(4-Ethylphenyl)-4,4,4-trifluoro-3-methylbutanoic acid(diastereomer mixture)

3.0 g of ethyl (3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoate(purity about 88%, about 9.16 mmol; diastereomer mixture) were dissolvedin the mixture of in each case 12.4 ml of methanol, THF and water, and5.49 g (137.35 mmol) of sodium hydroxide were added a little at a time.The reaction mixture was stirred at 40° C. for 9 h. After cooling, thevolatile solvents were substantially removed under reduced pressure andthe residue was diluted with water. The mixture was acidified byaddition of hydrochloric acid, and the aqueous phase was extracted threetimes with ethyl acetate. The combined organic phases were dried oversodium sulphate, and concentrated under reduced pressure, and theresidue was dried under high vacuum. This gave 2.61 g of the titlecompound as a crude product which was not purified any further(diastereomer ratio about 9:1).

LC-MS (Method 5): R_(t)=1.08 min, m/z=259 (M−H)⁻ (minor diastereomer);R_(t)=1.11 min, m/z=259 (M−H)⁻ (major diastereomer).

¹H-NMR (400 MHz, DMSO-d₆): major diastereomer: δ [ppm]=0.76 (d, 3H),1.17 (t, 3H), 2.54-2.66 (m, 4H), 3.10-3.29 (m, 1H), 3.56 (d, 1H),7.14-7.22 (m, 2H), 7.22-732 (m, 2H), 12.58 (br. s, 1H).

In a comparable manner (reaction temperature: RT to +40° C.; reactiontime: 9-12 h), the following carboxylic acids were prepared from thecorresponding esters:

Example 9A (3R)-4,4,4-Trifluoro-2-(4-fluorophenyl)-3-methylbutanoic acid(diastereomer mixture)

Diastereomer ratio about 9:1.

¹H-NMR (400 MHz, DMSO-d₆): major diastereomer: δ [ppm]=0.77 (d, 3H),3.18-3.30 (m, 1H), 3.67 (d, 1H), 7.17-7.24 (m, 2H), 7.39-7.47 (m, 2H),12.78 (br. s, 1H).

Example 91A(3R)-2-(4-Chloro-3-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid(diastereomer mixture)

Diastereomer ratio about 1:1.

GC-MS (Method 1): R_(t)=4.79 min; m/z=284 (M)⁺.

¹H-NMR (400 MHz, DMSO-d₆): both diastereomer: δ [ppm]=0.80/1.19 (each d,3H), 3.18-3.29 (m, 1H), 3.74/3.77 (each dd, 1H), 7.28 (d, 1H), 7.43-7.65(m, 2H), 12.91/13.24 (each br. s, 1H).

Examples 92A-95A (4-Chlorophenyl)(3,3-difluorocyclopentyl)acetic acid(isomers 1-4)

By preparative HPLC on a chiral phase, 4 g (14.56 mmol) of thediastereomer mixture of (4-chlorophenyl)(3,3-difluorocyclopentyl)aceticacid (Example 85A) were separated into the four enantiomerically purediastereomers [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; mobilephase: isohexane/(ethanol+0.2% trifluoroacetic acid+1% water) 95:5(v/v); flow rate: 20 ml/min; UV detection: 230 nm; temperature: 25° C.]:

Example 92A Isomer 1

Yield: 682 mg

R_(t)=8.2 min; chemical purity >94%

[Column: Daicel AD-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/(ethanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v); flowrate: 1.25 ml/min; UV detection: 230 nm; temperature: 30° C.].

LC-MS (Method 5): R_(t)=1.03 min; m/z=273 (M−H)⁻.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.46-1.82 (m, 3H), 1.96-2.27 (m, 3H),2.62-2.77 (m, 1H), 3.50 (d, 1H), 7.35 (d, 2H), 7.41 (d, 2H), 12.60 (br.s, 1H).

[α]_(D) ²⁰=54.2°, c=0.490, methanol.

Example 93A (Isomer 2)

Yield: 543 mg

R_(t)=9.53 min; chemical purity >97%

[Column: Daicel AD-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/(ethanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v); flowrate: 1.25 ml/min; UV detection: 230 m; temperature: 30° C.].

LC-MS (Method 5): R_(t)=1.03 min; m/z=273 (M−H)⁻.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.46-1.82 (m, 3H), 1.96-2.27 (m, 3H),2.63-2.77 (m, 1H), 3.50 (d, 1H), 7.35 (d, 2H), 7.41 (d, 2H), 12.61 (br.s, 1H).

[α]_(D) ²⁰=+53.0°, c=0.375, methanol.

Example 94A (Isomer 3)

Yield: 530 mg

R_(t)=10.36 min; chemical purity >92%

[Column: Daicel AD-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/(ethanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v); flowrate: 1.25 ml/min; UV detection: 230 am; temperature: 30° C.].

LC-MS (Method 5): R_(t)=1.04 min; m/z=273 (M−H)⁻.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.21-1.34 (m, 1H), 1.34-1.45 (m, 1H),1.76-2.17 (m, 3H), 2.27-2.42 (m, 1H), 2.60-2.75 (m, 1H), 3.49 (d, 1H),7.35 (d, 2H), 7.41 (d, 2H), 12.60 (br. s, 1H).

[α]_(D) ²⁰=−61.0°, c=0.340, methanol.

Example 95A (Isomer 4)

Yield: 560 mg

R_(t)=11.35 min; chemical purity >91%

[Column: Daicel AD-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/(ethanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v); flowrate: 1.25 ml/min; UV detection: 230 nm; temperature: 30° C.].

LC-MS (Method 5): R_(t)=1.04 min; m/z=273 (M−H)⁻.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.21-1.34 (m, 1H), 1.34-1.45 (m, 1H),1.77-2.17 (m, 3H), 2.27-2.42 (m, 1H), 2.60-2.75 (m, 1H), 3.49 (d, 1H),7.35 (d, 2H), 7.41 (d, 2H), 12.59 (br. s, 1H).

[α]_(D) ²⁰=+56.4°, c=0.485, methanol.

Example 96A Methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-4-methylpentanoate(diastereomer 1)

328 mg (1.23 mmol) of(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid weredissolved in 17.5 ml of dichloromethane, 263 mg (1.97 mmol) of1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixturewas stirred at room temperature for 30 min. 299 μl (3.7 mmol) ofpyridine and 315 mg (1.23 mmol) of methyl3-(3-amino-4-chlorophenyl)-4-methylpentanoate (enantiomer 1; Example17A) were then added, and the reaction mixture was stirred overnight.The reaction mixture was then concentrated under reduced pressure andthe crude product obtained was purified directly by preparative RP-HPLC(mobile phase methanol/water 80:20). This gave 237 mg of the targetcompound (38% of theory).

LC-MS (Method 5): R_(t)=1.43 min; m/z=504/506 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.68 (d, 3H), 0.80 (d, 3H), 0.85 (d,3H), 1.70-1.85 (m, 1H), 2.48-2.58 (m, 1H, partially obscured by DMSOsignal), 2.70-2.80 (m, 2H), 3.30-3.41 (m, 1H, partially obscured by H₂Osignal), 3.42 (s, 3H), 4.12 (d, 1H), 7.01 (dd, 1H), 7.31-7.37 (m, 2H),7.43-7.50 (m, 4H), 9.83 (s, 1H).

[α]_(D) ²⁰=+111°, c=0.25, methanol.

Example 97A Methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-4-methylpentanoate(diastereomer 2)

255 mg (0.96 mmol) of(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid weredissolved in 14 ml of dichloromethane, 205 mg (1.53 mmol) of1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixturewas stirred at room temperature for 30 min. 232 μl (2.87 mmol) ofpyridine and 245 mg (0.96 mmol) of methyl3-(3-amino-4-chlorophenyl)-4-methylpentanoate (enantiomer 2; Example18A) were then added, and the reaction mixture was stirred overnight.The reaction mixture was then concentrated under reduced pressure andthe crude product obtained was purified directly by preparative RP-HPLC(mobile phase methanol/water 80:20). This gave 228 mg of the targetcompound (47% of theory).

LC-MS (Method 5): R_(t)=1.43 min; m/z=504/506 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d#): δ [ppm]=0.67 (d, 3H), 0.80 (d, 3H), 0.85 (d,3H), 1.71-1.82 (m, 1H), 2.47-2.58 (m, 1H, partially obscured by DMSOsignal), 2.70-2.80 (m, 2H), 3.29-3.41 (m, 1H, partially obscured by H₂Osignal), 3.43 (s, 3H), 4.12 (d, 1H), 7.01 (dd, 1H), 7.33 (d, 1H), 7.35(d, 1H), 7.43-7.50 (m, 4H), 9.82 (s, 1H).

[α]_(D) ²⁰=+84.7°, c=0.325, methanol.

Example 98A tert-Butyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3-cyclopropylpropanoate(diastereomer 1)

45 mg (0.17 mmol) of(2S,3R-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid weredissolved in 1 ml of dichloromethane, 36 mg (0.27 mmol) of1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixturewas stirred at room temperature for 30 min. 41 μl (0.51 mmol) ofpyridine and 50 mg (0.17 mmol) of tert-butyl3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate (enantiomer 1;Example 30A), dissolved in 1 ml of dichloromethane, were then added, andthe reaction mixture was stirred for another 1 h. The reaction mixturewas then concentrated under reduced pressure and the crude productobtained was directly purified chromatographically on silica gel (mobilephase cyclohexane/ethyl acetate 20:1). This gave 78 mg of the targetcompound (85% of theory).

LC-MS (Method 7): R_(t)=1.52 min; m/z=542/544 (M−H)⁻.

Example 99A tert-Butyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3-cyclopropylpropanoate(diastereomer 2)

119 mg (0.45 mmol) of(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid weredissolved in 2 ml of dichloromethane, 95 mg (0.71 mmol) of1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixturewas stirred at room temperature for 30 min. 108 μl (1.34 mmol) ofpyridine and 132 mg (0.45 mmol) of tert-butyl3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate (enantiomer 2;Example 31A), dissolved in 2 ml of dichloromethane, were then added, andthe reaction mixture was stirred for another 1 h. The reaction mixturewas then concentrated under reduced pressure and the crude productobtained was directly purified chromatographically on silica gel (mobilephase cyclohexane/ethyl acetate 20:1). This gave 206 mg of the targetcompound as a colourless oil (85% of theory).

LC-MS (Method 7): R_(t)=1.53 min; m/z=542/544 (M−H)⁻.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.03-0.11 (m, 1H), 0.17-0.34 (m, 2H),0.45-0.55 (m, 1H), 0.80 (d, 3H), 0.88-1.00 (m, 1H), 1.21 (s, 9H),2.14-2.24 (m, 1H), 2.47-2.57 (m, 1H, obscured by DMSO signal), 2.58-2.66(m, 1H), 3.29-3.44 (m, 1H, partially obscured by H₂O signal), 4.14 (d,1H), 7.11 (dd, 1H), 7.37 (d, 1H), 7.40-7.51 (m, 5H), 9.82 (s, 1H).

The compounds listed in the table below were prepared in an analogousmanner:

Example Name/Structure/Starting materials Analytical data 100Atert-butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-phenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}phenyl)-3-(1-methylcyclopropyl)propanoate  

  from tert-butyl 3-(3-amino-4-chlorophenyl)-3-(1-methylcyclopropyl)propanoate and (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid LC-MS (Method7): Rt = 1.56 min; m/z = 556/558 (M − H)⁻. 101A tert-butyl3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-phenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}phenyl)-4-methoxy-4-methylpentanoate  

  from tert-butyl 3-(3-amino-4-chlorophenyl)-4-methoxy-4-methylpentanoate and (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid LC-MS (Method5): R_(t) = 1.48 min; m/z = 574/576 (M − H)⁻. 102A tert-butyl3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-phenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}phenyl)-3-(1-fluorocyclopropyl)propanoate  

  from tert-butyl 3-(3-amino-4-chlorophenyl)-3-(1-fluorocycloproyl)propanoate and (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid LC-MS (Method5): R_(t) = 1.46 min; m/z = 560/562 (M − H)⁻. 103A methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)- 3,4-dimethylpentanoate(diastereomer 1)  

  from methyl 3-(3-amino-4-chlorophenyl)- 3,4-dimethylpentanoate(enantiomer 1, Example 50A) and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid LC-MS (Method 7): R_(t) = 1.48min; m/z = 518/520 (M + H)⁺. ¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.56(d, 3H), 0.81 (dd, 6H), 1.29 (s, 3H), 1.82-1.93 (m, 1H), 2.58 (d, 1H),2.77 (d, 1H), 3.30-3.44 (m, 1H), 3.33 (s, 3H), 4.12 (d, 1H), 7.12 (dd,1H), 7.33 (d, 1H), 7.43- 7.50 (m, 5H), 9.81 (s, 1H). 104A methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)- 3,4-dimethylpentanoate(diastereomer 2)  

  from methyl 3-(3-amino-4-chlorophenyl)- 3,4-dimethylpentanoate(enantiomer 2, Example 51A) and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid LC-MS (Method 5): R_(t) = 1.48min; m/z = 518/520 (M + H)⁺. ¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.57(d, 3H), 0.81 (dd, 6H), 1.29 (s, 3H), 1.80-1.92 (m, 1H), 2.58 (d, 1H),2.77 (d, 1H), 3.29-3.46 (m, 1H), 3.35 (s, 3H), 4.12 (d, 1H), 7.12 (dd,1H), 7.33 (d, 1H), 7.42- 7.50 (m, 5H), 9.81 (s, 1H). 105A methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)- 3-cyclobutylbutanoate(diastereomer 1)  

  from methyl 3-(3-amino-4-chlorophenyl)- 3-cyclobutylbutanoate(enantiomer 1, Example 52A) and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid LC-MS (Method 5): R_(t) = 1.51min; m/z = 530/532 (M + H)⁺. ¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.80(d, 3H), 1.31 (s, 3H), 1.44-1.53 (m, 1H), 1.53-1.67 (m, 3H), 1.67-1.78(m, 2H), 2.46 (d, 1H), 2.47-2.60 (m, 1H), partially obscured by DMSOsignal), 2.70 (d, 1H), 3.36-3.46 (m, 1H), 3.38 (s, 3H), 4.12 (d, 1H),7.10 (dd, 1H), 7.34 (d, 1H), 7.42-7.51 (m, 5H), 9.81 (s, 1H). 106Amethyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)- 3-cyclobutylbutanoate(diastereomer 2)  

  from methyl 3-(3-amino-4-chlorophenyl)- 3-cyclobutylbutanoate(enantiomer 2, Example 53A) and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid LC-MS (Method 5): R_(t) = 1.51min; m/z = 530/532 (M + H)⁺. ¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.81(d, 3H), 1.31 (s, 3H), 1.43-1.53 (m, 1H), 1.53-1.67 (m, 3H), 1.67-1.78(m, 2H), 2.46 (d, 1H), 2.46-2.59 (m, 1H), partially obscured by DMSOsignal), 2.70 (d, 1H), 3.36-3.46 (m, 1H), 3.40 (s, 3H), 4.12 (d, 1H),7.10 (dd, 1H), 7.34 (d, 1H), 7.43-7.50 (m, 5H), 9.81 (s, 1H). 107Amethyl 3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)- 4-methylpentanoate(diastereomer 1)  

  from methyl 3-(3-amino-4-chlorophenyl)-4-methyl- pentanoate(enantiomer 1, Example 17A) and(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro- 3-methylbutanoic acid LC-MS(Method 5): R_(t) = 1.48 min; m/z = 498 (M + H)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.85 (d, 3H), 1.17 (t, 3H),1.70-1.84 (m, 1H), 2.45- 2.64 (m, 3H), partially obscured by DMSOsignal), 2.70-2.80 (m, 2H), 3.28-3.39 (m, 1H, partially obscured by H₂Osignal), 3.42 (s, 3H), 4.06 (d, 1H), 6.98 (dd, 1H), 7.21 (d, 2H),7.30-7.39 (m, 4H), 9.73 (s, 1H). 108A methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}phenyl)-4-methylpentanoate (diastereomer 1)  

  from methyl 3-(3-amino-4-chlorophenyl)-4-methyl- pentantoate(enantiomer 1, Example 17A) and(2S,3R)-2-(4-chloro-3-fluorophenyl)-4,4,4-trifluoro- 3-methylbutanoicacid LC-MS (Method 5): R_(t) = 1.43 min; m/z = 522/524 (M + H)⁺. ¹H-NMR(400 MHz, DMSO- d₆): δ [ppm] = 0.68 (d, 2.77H), major diastereomer),0.84 (t, 6H), 1.25 (d, 0.23H, minor diastereomer), 1.71-1.84 (m, 1H),2.46-2.60 (m, 1H, partially obscured by DMSO signal), 2.70-2.81 (m, 2H),3.36-3.49 (m, 1H), 3.43 (s, 3H), 4.15 (d, 1H), 7.02 (dd, 1H), 7.29-7.38(m, 3H), 7.50 (dd, 1H), 7.63 (t, 1H), 9.87 (s, 0.925H, majordiastereomer), 10.01 (s, 0.075H, minor diastereomer) (85% de). 109Amethyl 3-(4-chloro-3-{[(2S,3R)-4,4,4-trifluoro-2-(4-isopropylphenyl)-3-methylbutanoyl]amino}-phenyl)-4-methylpentanoate (diastereomer 1)  

  from methyl 3-(3-amino-4-chlorophenyl)-4-methyl- pentanoate(enantiomer 1, Example 17A) and(2S,3R)-4,4,4-trifluoro-2-(4-isopropylphenyl)- 3-methylbutanoic acidLC-MS (Method 5): R_(t) = 1.54 min; m/z = 512/514 (M + H)⁺. ¹H-NMR (400MHz, DMSO- d₆): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.85 (d, 3H), 1.19(d, 6H), 1.71-1.83 (m, 1H), 2.45-2.58 (m, 1H, obscured by DMSO signal),2.70-2.80 (m, 2H), 2.81-2.93 (m, 1H), 3.28- 3.39 (m, 1H, partiallyobscured by H₂O signal), 3.42 (s, 3H), 4.07 (d, 1H), 6.98 (dd, 1H), 7.24(d, 2H), 7.31-7.41 (m, 4H), 9.73 (s, 1H). 110A methyl3-(4-chloro-3-{[(2S,3R)-4,4,4-trifluoro-2-(4-fluorophenyl)-3-methylbutanoyl]amino}- phenyl)-4-methylpentanoate(diastereomer 1)  

  from methyl 3-(3-amino-4-chlorophenyl)-4-methyl- pentanoate(enantiomer 1, Example 17A) and(2S,3R)-4,4,4-trifluoro-2-(4-fluorophenyl)- 3-methylbutanoic acid LC-MS(Method 5): R_(t) = 1.36 min; m/z = 488/490 (M + H)⁺. ¹H-NMR (400 MHz,DMSO- d₆): δ [ppm] = 0.68 (d, 2.77H, major diastereomer), 0.80 (d, 3H),0.85 (d, 3H), 1.25 (d, 0.23H, minor diastereomer), 1.71-1.83 (m, 1H),2.45 (m, 1H), obscured by DMSO signal), 2.70-2.81 (m, 2H), 3.28-3.40 (m,1H, partially obscured by H₂O signal), 3.42 (s, 3H), 4.11 (d, 1H), 7.00(dd, 1H), 7.22 (t, 2H), 7.31-7.37 (m, 2H), 7.44- 7.54 (m, 2H), 9.80 (s,0.925H, major diastereomer), 9.93 (s, 0.075H, minor diastereomer) (85%de). 111A methyl 3-[4-chloro-3-({4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]butanoyl}amino)-phenyl]-4-methylpentanoate (diastereomer mixture)  

  from methyl 3-(3-amino-4-chlorophenyl)-4-methyl- pentanoate(enantiomer 1, Example 17A) and4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoroethyl)- phenyl]butanoicacid (diastereomer mixture) LC-MS (Method 5): R_(t) = 1.40 min; m/z =552/554 (M + H)⁺. 112A methyl3-[4-chloro-3-({(2S,3R)-2-[4-(2,2-difluoro-cyclopropyl)phenyl]-4,4,4-trifluoro-3-methyl-butanoyl}amino)phenyl]-4-methylpentanoate (diastereomer mixture)  

  from methyl 3-(3-amino-4-chlorophenyl)- 4-methylpentanoate (enantiomer1, Example 17A) and (2S,3R)-2-[4-(2,2-difluorocyclopropyl)phenyl]-4,4,4-trifluoro-3-methylbutanoic acid (diastereomer mixture) LC-MS(Method 5): R_(t) = 1.39 min; m/z = 546/548 (M + H)⁺. 113A methyl3-(3-{[(2S,3R)-2-(4-tert-butylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-4-chloro-phenyl)-4-methylpentanoate (diastereomer 1)  

  from methyl 3-(3-amino-4-chlorophenyl)-4-methyl- pentanoate(enantiomer 1, Example 17A) and(2S,3R)-2-(4-tert-butylphenyl)-4,4,4-trifluoro- 3-methylbutanoic acidLC-MS (Method 5): R_(t) = 1.52 min; m/z = 526/528 (M + H)⁺. ¹H-NMR (400MHz, DMSO- d₆): δ [ppm] = 0.68 (d, 3H, 0.79 (d, 3H), 0.85 (d, 3H), 1.27(s, 9H), 1.70-1.84 (m, 1H), 2.46-2.58 (m, 1H, partially obscured by DMSOsignal), 2.70-2.80 (m, 2H), 3.28-3.39 (m, 1H, partially obscured by H₂Osignal), 3.42 (s, 3H), 4.08 (d, 1H), 6.98 (dd, 1H), 7.31- 7.43 (m, 6H),9.72 (s, 0.96H, major diastereomer), 9.86 (s, 0.04H, minor diastereomer)(92% de). 114A methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-trifluoro-3-methyl-butanoyl]amino}phenyl)-4-methylpentanoate (diastereomer 1)  

  from methyl 3-(3-amino-4-chlorophenyl)-4-methyl- pentanoate(enantiomer 1, Example 17A) and (2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-trifluoro-3-methylbutanoic acid LC-MS (Method 4): R_(t) = 2.91min; m/z = 534/536 (M + H)⁺. 115A methyl3-(4-chloro-3-{[(2S,3R)-4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoyl]amino}- phenyl)-4-methylpentanoate(diastereomer 1)  

  from methyl 3-(3-amino-4-chlorophenyl)-4-methyl- pentanoate(enantiomer 1, Example 17A) and(2S,3R)-4,4,4-trifluoro-3-methyl-2-(4-methyl- phenyl)butanoic acid LC-MS(Method 5): R_(t) = 1.40 min; m/z = 484/486 (M + H)⁺. ¹H-NMR (400 MHz,DMSO- d₆): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.85 (d, 3H), 1.70-1.84 (m, 1H), 2.29 (s, 3H), 2.48- 2.57 (m, 1H), obscured by DMSOsignal), 2.70-2.80 (m, 2H), 3.29-3.40 (m, 1H, partially obscured by H₂Osignal), 3.42 (s, 3H), 4.05 (d, 1H), 6.99 (dd, 1H), 7.18 (d, 2H),7.29-7.38 (m, 4H), 9.73 (s, 0.94H, major diastereomer), 9.87 (s, 0.06H,minor diastereomer) (88% de). 116A methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}phenyl)-4-methylpentanoate (diastereomer 1)  

  from methyl 3-(3-amino-4-chlorophenyl)- 4-methylpentanoate (enantiomer1, Example 17A) and (2S,3R)-2-(4-chloro-3-methylphenyl)-4,4,4-trifluoro-3-methylbutanoic acid LC-MS (Method 5): R_(t) = 1.51min; m/z = 518/520 (M + H)⁺. ¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.68(d, 3H), 0.81 (d, 3H), 0.85 (d, 3H), 1.70- 1.83 (m, 1H), 2.23 (s, 3H),2.45- 2.59 (m, 1H, partially obscured by DMSO signal), 2.70-2.81 (m,2H), 3.28-3.41 (m, 1H, partially obscured by H₂O signal), 3.42 (s, 3H),4.07 (d, 1H), 7.00 (dd, 1H), 7.27-7.45 (m, 5H), 9.81 (s, 0.94H, majordiastereomer), 9.89 (s, 0.06H, minor diastereomer) (88% de). 117A methyl3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-difluorocyclopentyl)acetyl]amino}phenyl)- 4-methylpentanoate(isomer 1)  

  from methyl 3-(3-amino-4-chlorophenyl)- 4-methylpentanoate (enantiomer1, Example 17A) and (4-chlorophenyl)(3,3-difluorocyclopentyl)acetic acid(isomer 1) LC-MS (Method 5): R_(t) = 1.41 min; m/z = 512/514 (M + H)⁺.¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.67 (d, 3H), 0.85 (d, 3H),1.52-1.70 (m, 2H), 1.72-1.82 (m, 1H), 1.82-1.95 (m, 1H), 1.98-2.30 (m,3H), 2.46-2.60 (m, 1H, partially obscured by DMSO signal), 2.70-2.80 (m,2H), 2.80-2.93 (m, 1H), 3.43 (s, 3H), 3.78 (d, 1H), 7.02 (dd, 1H), 7.33(d, 1H), 7.37 (d, 1H), 7.44 (q, 4H), 9.78 (s, 1H). 118A methyl3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-difluorocyclopentyl)acetyl]amino}phenyl)- 4-methylpentanoate(isomer 2)  

  from methyl 3-(3-amino-4-chlorophenyl)- 4-methylpentanoate (enantiomer1, Example 17A) and (4-chlorophenyl)(3,3-difluorocyclopentyl)acetic acid(isomer 2) LC-MS (Method 5): R_(t) = 1.41 min; m/z = 512/514 (M + H)⁺.¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.67 (d, 3H), 0.85 (d, 3H),1.52-1.69 (m, 2H), 1.72-1.81 (m, 1H), 1.81-1.96 (m, 1H), 1.98-2.30 (m,3H), 2.46-2.60 (m, 1H, partially obscured by DMSO signal), 2.70-2.80 (m,2H), 2.80-2.93 (m, 1H), 3.43 (s, 3H), 3.78 (d, 1H), 7.02 (dd, 1H), 7.34(d, 1H), 7.36 (d, 1H), 7.44 (q, 4H), 9.78 (s, 1H). 119A methyl3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-difluorocyclopentyl)acetyl]amino}phenyl)- 4-methylpentanoate(isomer 3)  

  from methyl-3-(3-amino-4-chlorophenyl)- 4-methylpentanoate (enantiomer1, Example 17A) and (4-chlorophenyl)(3,3-difluorocyclopentyl)acetic acid(isomer 3) LC-MS (Method 5): R_(t) = 1.42 min; m/z = 512/514 (M + H)⁺.¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.67 (d, 3H), 0.85 (d, 3H),1.21-1.35 (m, 1H), 1.45-1.58 (m, 1H), 1.72-1.83 (m, 1H), 1.85-2.20 (m,3H), 2.28-2.43 (m, 1H), 2.47-2.60 (m, 1H, partially obscured by DMSOsignal), 2.70-2.90 (m, 3H), 3.44 (s, 3H), 3.75 (d, 1H), 7.02 (dd, 1H),7.33 (d, 1H), 7.37 (d, 1H), 7.44 (q, 4H), 9.74 (s, 1H). 120A methyl3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-difluorocyclopentyl)acetyl]amino}phenyl)- 4-methylpentanoate(isomer 4)  

  from methyl 3-(3-amino-4-chlorophenyl)- 4-methylpentanoate (enantiomer1, Example 17A) and (4-chlorophenyl)(3,3-difluorocyclopentyl)acetic acid(isomer 4) LC-MS (Method 5): R_(t) = 1.42 min; m/z = 512/514 (M + H)⁺.¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.68 (d, 3H), 0.86 (d, 3H),1.21-1.35 (m, 1H), 1.45-1.58 (m, 1H), 1.71-1.83 (m, 1H), 1.85-2.20 (m,3H), 2.29-2.44 (m, 1H), 2.46-2.61 (m, 1H, partially obscured by DMSOsignal), 2.70-2.90 (m, 3H), 3.43 (s, 3H), 3.75 (d, 1H), 7.02 (dd, 1H),7.34 (d, 1H), 7.36 (d, 1H), 7.44 (q, 4H), 9.74 (s, 1H).

Example 121A Methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl-3-(2,2-difluorocyclopropyl)propanoateand methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-5,5-difluorohexanoate

330 mg (1.24 mmol) of(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid weredissolved in 10 ml of dichloromethane, 264 mg (1.98 mmol) of1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixturewas stirred at room temperature for 30 min. 300 μl (3.71 mmol) ofpyridine and 360 mg of the mixture consisting of methyl3-(3-amino-4-chlorophenyl)-3-(2,2-difluorocyclopropyl)propanoate andmethyl 3-(3-amino-4-chlorophenyl)-5,5-difluorohexanoate (Example 59A),dissolved in 1 ml of dichloromethane, were then added, and the reactionmixture was stirred for a further 1 h. The reaction mixture was thenconcentrated under reduced pressure and the crude product obtained wasdirectly purified chromatographically on silica gel (mobile phasecyclohexane/ethyl acetate 20:1). This gave 479 mg of the mixture of thetwo target compounds.

LC-MS (Method 5): R_(t)=1.33 min; m/z=538/540/542 (M+H)⁺.

Examples 122A-125A

476 mg of the mixture of methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-(2,2-difluorocyclopropyl)propenoateand methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-5,5-difluorohexanoate(Example 121A) were separated further by preparative HPLC on a chiralphase [column: Daicel Chiralpak AZ-H, 5 μm, 250 mm×20 mm; mobile phase:isobhexane/isopropanol 95:5 (v/v); flow rate: 15 ml/min; UV detection:220 nm; temperature: 30° C.]. The material initially obtained for peak 2and peak 3 was combined and then separated by another preparative HPLCon a chiral phase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm;mobile phase: isohexane/isopropanol 95:5 (v/v); flow rate: 15 ml/min; UVdetection: 220 nm; temperature: 30° C.].

Example 122A Methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-5,5-difluorohexanoate(diastereomer 1)

Yield: 100 mg

R_(t)+8.42 min; chemical purity >99%, >99% de

[Column: Daicel AZ-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/(isopropanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v);flow rate: 1 ml/min; UV detection: 220 nm; temperature: 30° C.].

LC-MS (Method 5): R_(t)=1.33 inn m/z=540/542 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.80 (d, 3H), 1.46 (t, 3H), 2.19-2.32(m, 2H), 2.46-2.60 (m, 1H, partially obscured by DMSO signal), 2.69-2.78(m, 11H), 3.20-3.30 (m, 1H), 3.30-3.43 (m, 1H, obscured by H₂O signal),3.48 (s, 3H), 4.12 (d, 1H), 7.14 (dd, 1H), 7.37 (d, 1H), 7.42 (d, 1H),7.43-7.50 (m, 4H), 9.84 (s, 1H).

Example 123A Methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-5,5-difluorohexanoate(diastereomer 2)

Yield: 96 mg

R_(t)=10.14 win; chemical purity >94%, >99% de

[Column: Daicel AZ-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/(isopropanol+0.2% trifluroacetic acid+1% water) 95:5 (v/v);flow rate: 1 ml/min; UV detection: 220 nm; temperature: 30° C.].

LC-MS (Method 5): R_(t)=1.33 min; m/z=540/542 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.80 (d, 3H), 1.47 (t, 3H), 2.19-2.32(m, 2H), 2.46-2.60 (m, 1H, partially obscured by DMSO signal), 2.69-2.78(m, 1H), 3.20-3.30 (m, 1H), 3.30-3.43 (m, 1H, obscured by H₂O signal),3.46 (s, 3H), 4.12 (d, 1H), 7.14 (dd, 1H), 7.37 (d, 1H), 7.41 (d, 1H),7.43-7.50 (m, 4H), 9.84 (s, 1H).

Example 124A Methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3-(2,2-difluorocyclopropyl)propanoate(isomer 1)

Yield: 124 mg

R_(t)=9.00 min; chemical purity >96%

[Column: Daicel AZ-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/(isopropanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v);flow rate: 1 ml/min; UV detection: 220 nm; temperature: 30° C.].

LC-MS (Method 5): R_(t)=1.34 min; m/z=538/540 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.80 (d, 3H) 1.06-1.18 (m, 1H),1.38-1.51 (m, 1H), 2.01-2.16 (m, 1H), 2.64-2.82 (m, 3H), 3.28-3.54 (m,1H, partially obscured by H₂O signal), 3.50 (s, 3H), 4.12 (d, 1H), 7.22(dd, 1H), 7.41 (d, 1H), 7.43-7.50 (m, 5H), 9.88 (s, 1H).

Example 125A Methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3-(2,2-difluorocyclopropyl)propanoate(isomer 2)

Yield: 118 mg

R_(t)9.47 min; chemical purity >99%

[Column: Daicel AZ-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/(isopropanol+0.2% trifluoroacetic acid+1% water) 95:5 (v/v);flow rate: 1 ml/min; UV detection: 220 nm; temperature: 30° C.].

LC-MS (Method 5): R_(t)=1.33 min; m/z=538/540 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.80 (d, 3H), 1.06-1.18 (m, 1H),1.38-1.52 (m, 1H), 2.01-2.15 (m, 1H), 2.63-2.83 (m, 3H), 3.28-3.58 (m,1H, partially obscured by H₂O signal), 3.49 (s, 3H), 4.12 (d, 1H), 7.21(dd, 1H), 7.40 (d, 1H), 7.42-7.50 (m, 5H), 9.87 (s, 1H).

Example 126A tert-Butyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3-(3,3-difluorocyclobutyl)propanoate(diastereomer mixture)

A solution of 76 mg (0.29 mmol) of(2S,3R)-2-(4-chlorophenyl)-4,4-trifluoro-3-methylbutanoic acid, 45 mg(0.13 mmol) of tert-butyl3-(3-amino-4-chlorophenyl)-3-(3,3-difluorocyclobutyl)-propanoate, 119 mg(0.31 mmol) of O-(1H-7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (HATU) and 0.51 ml of pyridine in 1 ml of DMF wasstirred at room temperature overnight. After the reaction had ended, themixture was directly, without further work-up, separated into itscomponents by preparative HPLC. This gave 19 mg (25% of theory) of thetitle compound as a colourless oil.

LC-MS (Method 5): R_(t)=1.47 min; m/z=592/594 (M−H)⁻.

The compounds listed in the table below were prepared in an analogousmanner:

Example Name/Structure/Starting materials Analytical data 127Atert-butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3-cyclobutylpropanoate  

  from (+/−)-tert-butyl 3-(3-amino-4-chlorophenyl)-3-cyclobutylpropanoate and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid LC-MS (Method5): R_(t) = 1.57 min; m/z = 556 (M − H)⁻. ¹H-NMR (400 MHz, DMSO- d₆):both diastereomers: δ [ppm] = 0.80 (d, 3H), 1.15/1.18 (2s, together 9H),1.46-1.62 (m, 2H), 1.62-1.76 (m, 3H), 1.96- 2.06 (m, 1H), 2.16-2.28 (m,1H), 2.32-2.48 (m, 2H), 2.76- 2.87 (m, 1H), 3.35-3.45 (m, 1H), 4.13/4.14(2d, together 1H), 7.00 (dt, 1H), 7.34 (d, 1H), 7.36-7.53 (m, 5H,9.79/9.80 (2s, together 1H). 128A tert-butyl3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-4-cyclopropylbutanoate (diastereomer mixture)  

  from tert-butyl 3-(3-amino-4-chlorophenyl)- 4-cyclopropylbutanoate and(+)-(2S,3R)- 2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acidLC-MS (Method 5): R_(t) = 1.62 min; m/z = 556/558 (M − H)⁻. 129A ethyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropyl-2-methylpropanoate (diastereomer mixture)  

  from ethyl 3-(3-amino-4-chlorophenyl)-3-cyclo-propyl-2-methylpropanoat (diastereomer mixture) and(+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro- 3-methylbutanoic acidLC-MS (Method 7): R_(t) = 1.49 min; m/z = 530/532 (M + H)⁺. 130A methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)- 3-cyclopropylbutanoate(diastereomer mixture)  

  from methyl 3-(3-amino-4-chlorophenyl)-3-cyclo- propylbutanoate(racemate) and (+)-(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid LC-MS (Method5): R_(t) = 1.41 min; m/z = 516/518 (M + H)⁺.

Example 131A 2-(1-Methylcyclopropyl)ethanol

11.23 g (87.1 mmol) of zinc/copper pair were taken up in 50 ml ofdiethyl ether, and 6.76 ml (92.9 mmol) of chloroiodomethane were addedat room temperature. 5.84 ml (58.1 mmol) of 3-methylbut-3-en-1-ol,dissolved in 10 ml of diethyl ether, were then added dropwise. After theaddition had ended, the reaction mixture was heated to 40° C. andstirred at this temperature overnight. After cooling, the reaction wasfiltered off with suction through kieselguhr, and the kieselguhr waswashed repeatedly with diethyl ether. The combined filtrates were washedwith saturated aqueous sodium bicarbonate solution and with water, driedover magnesium sulphate and then concentrated to dryness under reducedpressure. The residue obtained was purified by chromatography on silicagel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.58 g (62%of theory) of the title compound.

GC-MS (Method 1): R_(t)=1.23 min; m/z=100 (M)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]0.24-0.29 (m, 2H), 0.29-0.34 (m, 2H),1.05 (s, 3H), 1.37 (t, 1H), 1.53 (t, 2H), 3.74-3.80 (m, 2H).

The following compound was obtained analogously to Synthesis Example 1A:

Example Name/Structure/Starting materials Analytical data 132A

GC-MS (Method 6): R_(t) = 3.86 min; m/z = 214 (M + NH₄)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.25-0.31 (m, 2H), 0.31-0.37 (m, 2H), 0.98 (s,3H), 1.43 (s, 9H), 2.06-2.11 (m, 2H), 5.76-5.83 (m, 1H), 6.72-6.82 (m,1H). from tert-butyl (triphenyl-λ⁵-phosphanylidene)- acetate and2-(1-methylcyclopropyl)ethanol

The following compound was obtained analogously to Synthesis Example4A/5A:

Example Name/Structure/Starting materials Analytical data 133A

LC-MS (Method 5): R_(t) = 1.42 min; m/z = 322 (M + H)⁺. ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.04-0.10 (m, 2H), 0.17-0.24 (m, 2H), 0.85 (s, 3H),1.46 (s, 9H), 3.02 (s, 2H), 5.40 (br. s, 2H), 5.82 (s, 1H), 6.62 (dd,1H), 6.88 (d, 1H), 7.17 (d, 1H). from tert-butyl(2E)-4-(1-methylcyclopropyl)- but-2-enoate and 5-bromo-2-chloroaniline

Example 134A tert-Butyl3-(3-amino-4-chlorophenyl)-4-(1-methylcyclopropyl)butanoate

187 mg (0.58 mmol) of tert-butyl(2E/Z)-3-(3-amino-4-chlorophenyl)-4-(1-methylcyclopropyl)but-2-enoatewere dissolved in 10 ml of ethyl acetate, and 11 mg (0.06 mmol) ofplatinum (IV) oxide were added. At RT, the reaction mixture was stirredunder an atmosphere of hydrogen at atmospheric pressure overnightAnother 11 mg (0.06 mmol) of platinum(IV) oxide were added, and themixture was then once more stirred at RT under an atmosphere of hydrogenat atmospheric pressure overnight. The reaction mixture was thenfiltered off with suction through kieselguhr, and the filtrate wasconcentrated. This gave 36 mg (19% of theory) of the target compound.

LC-MS (Method 5): R_(t)=1.37 min; m/z=324 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=−0.10-−0.03 (m, 1H), −0.03-0.04 (m,1H), 0.13-0.25 (m, 2H), 0.95 (s, 3H), 1.27 (s, 9H), 1.40-1.52 (m, 2H),2.24-2.33 (m, 1H), 2.47-2.58 (m, 1H, partially obscured by DMSO signal),2.95-3.05 (m, 1H), 5.19 (br. s, 2H), 6.41 (dd, 1H), 6.65 (d, 1H), 7.05(d, 1H).

The following compound was prepared analogously to Synthesis Example99A:

Example Name/Structure/Starting materials Analytical data 135A

LC-MS (Method 8): R_(t) = 3.27 min; m/z = 570/571 (M − H)⁻. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = −0.14-−0.07 (m, 1H), −0.07- 0.02 (m, 1H),0.12-0.19 (m, 1H), 0.19-0.25 (m, 1H), 0.80 (d, 3H), 0.93 (d, 3H), 1.19(2s, 9H), 1.39-1.55 (m, 2H), 2.26-2.38 (m, 1H), 2.48-2.63 (m, 1H,partially obscured by DMSO signal), 3.05-3.16 (m, 1H), 3.29-3.44 (m, 1H,partially obscured by H₂O signal), 4.14 (dd, 1H), 7.06 (d, 1H), 7.34 (d,1H), 7.39-7.51 (m, 5H), 9.80 (d, 1H). from tert-butyl3-(3-amino-4-chlorophenyl)-4-(1-methylcyclo- propyl)butanoate and(2S,3R)-2-(4-chlorophenyl)-4,4,4- trifluoro-3-methylbutanoic acid

WORKING EXAMPLES Example 1(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluo-3-methylbutanoyl]amino}phenyl)-4-methylpentanoicacid (diastereomer 1)

4 ml of concentrated acetic acid and 2 ml of concentrated hydrochloricacid were added to 225 mg (0.45 mmol) of methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-methylpentanoate(diastereomer 1; Example 96A). The reaction mixture was stirred at 100°C. for 2 h. After cooling, the reaction mixture was added to ice-water,and the crystals formed were filtered off with suction. The crystalswere washed twice with water and then dried in a high vacuum dryingcabinet at 40° C. overnight. This gave 193 mg (88% of theory) of thetitle compound as a white solid.

LC-MS (Method 7): R_(t)=1.30 min; m/z=490/492 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.68 (d, 3H), 0.80 (d, 3H), 0.84 (d,3H), 1.70-1.80 (m, 1H), 2.36-2.48 (m, 1H), 2.61-2.70 (m, 1H), 2.70-2.80(m, 1H), 3.29-3.43 (m, 1H, partially obscured by H₂O signal), 4.13 (d,1H), 7.00 (dd, 1H), 7.31-7.37 (m, 2H), 7.43-7.50 (m, 4H), 9.82 (s, 1H),11.95 (br. s, 1H).

[α]_(D) ²⁰=+111°, c=0.285, methanol.

Example 2(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-methylpentanoicacid (diastereomer 2)

4 ml of concentrated acetic acid and 2 ml of concentrated hydrochloricacid were added to 218 mg (0.43 mmol) of methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-methylpentanoate(diastereomer 2; Example 97A). The reaction mixture was stirred at 100°C. for 2 h. After cooling, the reaction mixture was added to ice-water,and the crystals formed were filtered off with suction. The crystalswere washed twice with water and then dried in a high vacuum dryingcabinet at 40° C. overnight. This gave 188 mg (89% of theory) of thetitle compound as a white solid.

LC-MS (Method 7): R_(t)=1.30 min; m/z=490/492 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.67 (d, 3H), 0.80 (d, 3H), 0.84 (d,3H), 1.69-1.80 (m, 1H), 2.39-2.48 (m, 1H), 2.62-2.70 (m, 1H), 2.71-2.79(m, 1H), 3.29-3.44 (m, 1H, partially obscured by H₂O signal), 4.13 (d,1H), 7.00 (dd, 1H) 7.32-7.38 (m, 2H), 7.41-7.51 (m, 4H), 9.82 (s, 1H),11.96 (br. s, 1H).

[α]_(D) ²⁰=+82°, c=0.275, methanol.

The compounds listed in the table below were prepared in an analogousmanner:

Example Name/Structure/Starting material Analytical data  3

LC-MS (Method 5): R_(t) = 1.30 min; m/z = 504/506 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.55 (d, 3H), 0.80 (d, 6H), 1.30 (s, 3H),1.75-1.88 (m, 1H), 2.46-2.58 (d, 1H, obscured by DMSO signal), 2.69 (d,1H), 3.28-3.45 (m, 1H, partially obscured by H₂O signal), 4.13 (d, 1H),7.12 (dd, 1H), 7.33 (d, 1H), 7.43-7.51 (m, 5H), 9.81 (s, 1H), 11.75 (br.s, 1H). [α]_(D) ²⁰ = +95°, c = 0.285, methanol. from methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3,4- dimethylpentanoate(diastereomer 1)  4

LC-MS (Method 5): R_(t) = 1.30 min; m/z = 504/506 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.56 (d, 3H), 0.80 (d, 6H), 1.30 (s, 3H),1.75-1.89 (m, 1H), 2.46-2.57 (d, 1H, obscured by DMSO signal), 2.69 (d,1H), 3.29-3.45 (m, 1H, partially obscured by H₂O signal), 4.13 (d, 1H),7.12 (dd, 1H), 7.32 (d, 1H), 7.42-7.48 (m, 4H), 7.49 (d, 1H), 9.81 (s,1H), 11.75 (br. s, 1H). [α]_(D) ²⁰ = +105.7°, c = 0.305, methanol. frommethyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3,4- dimethylpentanoate(diastereomer 2)  5

LC-MS (Method 5): R_(t) = 1.32 min; m/z = 516/518 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.80 (d, 3H), 1.31 (s, 3H), 1.41- 1.52 (m, 1H),1.52-1.66 (m, 3H), 1.66- 1.78 (m, 2H), 2.37 (d, 1H), 2.45-2.58 (m, 1H,obscured by DMSO signal), 2.64 (d, 1H), 3.28-3.47 (m, 1H, partiallyobscured by H₂O signal), 4.13 (d, 1H), 7.10 (dd, 1H), 7.33 (d, 1H),7.40-7.52 (m, 5H), 9.81 (s, 1H), 11.83 (br. s, 1H). [α]_(D) ²⁰ = +105°,c = 0.250, methanol. from methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3- cyclobutylbutanoate(diastereomer 1)  6

LC-MS (Method 5): R_(t) = 1.32 min; m/z = 516/518 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.80 (d, 3H), 1.31 (s, 3H), 1.42- 1.52 (m, 1H),1.52-1.67 (m, 3H), 1.67-1.79 (m, 2H), 2.37 (d, 1H), 2.45-2.58 (m, 1H,obscured by DMSO signal), 2.64 (d, 1H), 3.30-3.47 (m, 1H, partiallyobscured by H₂O signal), 4.13 (d, 1H), 7.10 (dd, 1H), 7.33 (d, 1H),7.41-7.52 (m, 5H), 9.81 (s, 1H), 11.84 (br. s, 1H). [α]_(D) ²⁰ = +100°,c = 0.30, methanol. from methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3- cyclobutylbutanoate(diastereomer 2)  7

LC-MS (Method 4): R_(t) = 1.54 min; m/z = 500/502 (M − H)⁻. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.77-0.85 (m, 5H), 0.87-1.02 (m, 1H), 1.15-1.28(m, 2H), 1.42 (s, 3H), 2.62-2.72 (m, 1H), 3.01 (d, 1H), 3.28-3.43 (m,1H, partially obscured by H₂O signal), 4.09-4.17 (m, 1H), 7.08 (dd, 1H),7.38- 7.53 (m, 6H), 9.92 (d, 1H). from methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-3- cyclopropylbutanoate(diastereomer mixture)  8

LC-MS (Method 5): R_(t) = 1.32 min; m/z = 484 (M + H)⁺. ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.84 (d, 3H), 1.17 (t,3H), 1.68-1.81 (m, 1H), 2.36-2.47 (m, 1H), 2.56-2.69 (m, 1H), 2.70-2.79(m, 1H), 3.27-3.40 (m, 1H, partially obscured by H₂O signal), 4.07 (d,1H), 6.98 (dd, 1H), 7.20 (d, 2H), 7.30-7.41 (m, 4H), 9.73 (s, 1H), 11.95(br. s, 1H). from methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-phenyl)-4- methylpentanoate(diastereomer 1)  9

LC-MS (Method 5): R_(t) = 1.28 min; m/z = 508/510 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.68 (d, 2.79H, major diastereomer), 0.84 (t,6H), 1.25 (d, 0.21H, minor diastereomer), 1.69-1.81 (m, 1H), 2.39-2.48(m, 1H), 2.61-2.70 (m, 1H), 2.70-2.81 (m, 1H), 3.37-3.48 (m, 1H), 4.15(d, 1H), 7.01 (dd, 1H), 7.29-7.38 (m, 3H), 7.50 (dd, 1H), 7.62 (t, 1H),9.87 (s, 0.93H, major diastereomer), 10.01 (s, 0.07H, minordiastereomer), 11.96 (br. s, 1H) (86% de). from methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-fluoro-phenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}phenyl)-4-methylpentanoate (diastereomer 1) 10

LC-MS (Method 5): R_(t) = 1.35 min; m/z = 498/500 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.84 (d, 3H), 1.19(d, 6H), 1.67-1.80 (m, 1H), 2.36-2.47 (m, 1H), 2.60-2.70 (m, 1H),2.70-2.79 (m, 1H), 2.81-2.93 (m, 1H), 3.26-3.40 (m, 1H, obscured by H₂Osignal), 4.07 (d, 1H), 6.98 (dd, 1H), 7.20-7.28 (m, 2H), 7.30-7.43 (m,4H), 9.73 (s, 1H), 11.95 (br. s, 1H). from methyl3-(4-chloro-3-{[(2S,3R)-4,4,4-trifluoro-2-(4-isopropylphenyl)-3-methylbutanoyl]amino}phenyl)- 4-methylpentanoate(diastereomer 1) 11

LC-MS (Method 5): R_(t) = 1.19 min; m/z = 474/476 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.68 (d, 2.76H, major diastereomer), 0.80 (d,3H), 0.84 (d, 3H), 1.25 (d, 0.24H, minor diastereomer), 1.68-1.80 (m,1H), 2.36-2.47 (m, 1H), 2.60-2.70 (m, 1H), 2.70-2.80 (m, 1H), 3.29-3.44(m, 1H, partially obscured by H₂O signal), 4.12 (d, 1H), 7.00 (dd, 1H),7.22 (t, 2H), 7.31-7.37 (m, 2H), 7.45- 7.52 (m, 2H), 9.80 (s, 0.92H,major diastereomer), 9.94 (s, 0.08H, minor diastereomer), 11.96 (br. s,1H) (84% de). from methyl 3-(4-chloro-3-{[(2S,3R)-4,4,4-trifluoro-2-(4-fluorophenyl)-3-methylbutanoyl]amino}phenyl)- 4-methylpentanoate(diastereomer 1) 12

LC-MS (Method 5): R_(t) = 1.26 min; m/z = 538/540 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.64-0.71 (m, 3H), 0.79 (d, 3H), 0.84 (d, 3H),1.68-1.81 (m, 1H), 2.38- 2.47 (m, 1H), 2.61-2.69 (m, 1H), 2.70- 2.80 (m,1H), 3.28-3.44 (m, 1H, partially obscured by H₂O signal), 3.64 (q, 2H),4.11 (d, 1H), 6.99 (d, 1H), 7.30-7.39 (m, 4H), 7.46 (d, 2H), 9.80 (s,1H), 11.95 (br. s, 1H). from methyl3-[4-chloro-3-(4,4,4-trifluoro-3-methyl-2-[4-(2,2,2-trifluoroethyl)phenyl]-butanoyl}amino)phenyl]- 4-methylpentanoate(diastereomer mixture) 13

LC-MS (Method 5): R_(t) = 1.26 min; m/z = 532/534 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.84 (d, 3H),1.68-1.80 (m, 1H), 1.87-2.04 (m, 2H), 2.36-2.47 (m, 1H), 2.61-2.69 (m,1H), 2.70-2.79 (m, 1H), 2.93-3.06 (m, 1H), 3.29-3.44 (m, 1H, partiallyobscured by H₂O signal), 4.10 (d, 1H), 6.99 (dd, 1H), 7.27 (d, 2H), 7.33(d, 1H), 7.37 (s, 1H), 7.42 (d, 2H), 9.77 (s, 1H), 11.95 (br. s, 1H).from methyl 3-[4-chloro-3-({(2S,3R)-2-[4-(2,2-difluoro-cyclopropyl)phenyl]-4,4,4-trifluoro-3-methylbutanoyl}amino)phenyl]-4-methylpentanoate (diastereomer mixture) 14

LC-MS (Method 5): R_(t) = 1.39 min; m/z = 512/514 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.84 (d, 3H), 1.27(s, 9H), 1.68-1.80 (m, 1H), 2.36-2.47 (m, 1H), 2.60-2.69 (m, 1H),2.70-2.79 (m, 1H), 3.27-3.43 (m, 1H, partially obscured by H₂O signal),4.08 (d, 1H), 6.97 (dd, 1H), 7.30- 7.44 (m, 6H), 9.73 (s, 0.96H, majordiastereomer), 9.86 (s, 0.04H, minor diastereomer), 11.95 (br. s, 1H)(92% de). from methyl 3-(3-{[(2S,3R)-2-(4-tert-butylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-4-chlorophenyl)- 4-methylpentanoate(diastereomer 1) 15

LC-MS (Method 5): R_(t) = 1.24 min; m/z = 520/522 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.68 (d, 3H), 0.80-0.88 (m, 6H), 1.68-1.81 (m,1H), 2.35-2.48 (m, 1H), 2.61-2.70 (m, 1H), 2.70-2.81 (m, 1H), 3.36-3.49(m, 1H), 3.87 (s, 3H), 4.10 (d, 1H), 7.01 (t, 2H), 7.23 (d, 1H),7.32-7.37 (m, 2H), 7.43 (d, 1H), 9.81 (s, 1H), 11.96 (br. s, 1H). frommethyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methoxyphenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-methylpentanoate (diastereomer 1) 16

LC-MS (Method 8): R_(t) = 2.70 min; m/z = 470/472 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.68 (d, 3H), 0.79 (d, 3H), 0.84 (d, 3H),1.68-1.80 (m, 1H), 2.29 (s, 3H), 2.36-2.47 (m, 1H), 2.61-2.69 (m, 1H),2.70-2.79 (m, 1H), 3.26-3.40 (m, 1H, partially obscured by H₂O signal),4.05 (d, 1H), 6.98 (dd, 1H), 7.17 (d, 2H), 7.29-7.39 (m, 4H), 9.73 (s,0.96H, major diastereomer), 9.87 (s, 0.04H, minor diastereomer), 11.95(br. s, 1H) (92% de). from methyl3-(4-chloro-3-{[(2S,3R)-4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)-butanoyl]amino}phenyl)- 4-methylpentanoate(diastereomer 1) 17

LC-MS (Method 5): R_(t) = 1.33 min; m/z = 504/506 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.68 (d, 3H), 0.75-0.89 (m, 6H), 1.68-1.81 (m,1H), 2.33 (s, 3H), 2.36- 2.59 (m, 1H, partially obscured by DMSOsignal), 2.61-2.70 (m, 1H), 2.70- 2.81 (m, 1H), 3.25-3.43 (m, 1H,partially obscured by H₂O signal), 4.07 (d, 1H), 7.00 (d, 1H), 7.25-7.39(m, 3H), 7.39- 7.47 (m, 2H), 9.81 (s, 1H), 11.95 (br. s, 1H). frommethyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-3-methylphenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}phenyl)-4-methylpentanoate (diastereomer 1) 18

LC-MS (Method 8): R_(t) = 2.71 min; m/z = 498/500 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.67 (d, 3H), 0.84 (d, 3H), 1.52- 1.69 (m, 2H),1.70-1.81 (m, 1H), 1.81- 1.96 (m, 1H), 1.98-2.31 (m, 3H), 2.36- 2.47 (m,1H), 2.61-2.70 (m, 1H), 2.70-2.80 (m, 1H), 2.80-2.93 (m, 1H), 3.78 (d,1H), 7.02 (dd, 1H), 7.31-7.39 (m, 2H), 7.44 (q, 4H), 9.78 (s, 1H), 11.95(br. s, 1H). from methyl 3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-difluorocyclopentyl)acetyl]amino}phenyl)-4- methylpentanoate (isomer 1)19

LC-MS (Method 8): R_(t) = 2.71 min; m/z = 498/500 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.67 (d, 3H), 0.85 (d, 3H), 1.52- 1.69 (m, 2H),1.70-1.81 (m, 1H), 1.81- 1.96 (m, 1H), 1.98-2.31 (m, 3H), 2.36- 2.48 (m,1H), 2.61-2.70 (m, 1H), 2.70- 2.79 (m, 1H), 2.80-2.93 (m, 1H), 3.79 (d,1H), 7.01 (dd, 1H), 7.32-7.39 (m, 2H), 7.43 (q, 4H), 9.77 (s, 1H), 11.95(br. s, 1H). from methyl 3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-difluorocyclopentyl)acetyl]amino}phenyl)-4- methylpentanoate (isomer 2)20

LC-MS (Method 8): R_(t) = 2.71 min; m/z = 498/500 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.67 (d, 3H), 0.84 (d, 3H), 1.20- 1.34 (m, 1H),1.45-1.56 (m, 1H), 1.70- 1.81 (m, 1H), 1.85-2.19 (m, 3H), 2.28- 2.40 (m,1H), 2.40-2.53 (m, 1H, partially obscured by DMSO signal), 2.61-2.70 (m,1H), 2.70-2.90 (m, 2H), 3.75 (d, 1H), 7.02 (dd, 1H), 7.34 (d, 1H), 7.37(d, 1H), 7.44 (q, 4H), 9.74 (s, 1H), 11.95 (br. s, 1H). from methyl3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-difluorocyclopentyl)acetyl]amino}phenyl)-4- methylpentanoate (isomer 3)21

LC-MS (Method 8): R_(t) = 2.71 min; m/z = 498/500 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.68 (d, 3H), 0.85 (d, 3H), 1.20- 1.34 (m, 1H),1.45-1.56 (m, 1H), 1.70- 1.81 (m, 1H), 1.85-2.20 (m, 3H), 2.29- 2.41 (m,1H), 2.41-2.53 (m, 1H, partially obscured by DMSO signal), 2.62-2.70 (m,1H), 2.70-2.90 (m, 2H), 3.75 (d, 1H), 7.02 (dd, 1H), 7.32-7.39 (m, 2H),7.44 (q, 4H), 9.73 (s, 1H), 11.95 (br. s, 1H). from methyl3-(4-chloro-3-{[(4-chlorophenyl)-(3,3-difluorocyclopentyl)acetyl]amino}phenyl)-4- methylpentanoate (isomer 4)

Example 22(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoicacid (diastereomer 2)

78 ing (0.14 mmol) of tert-butyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoate(diastereomer 2; Example 99A) were dissolved in 10 ml ofdichloromethane, and 0.33 ml (4.3 mmol) of trifluoroacetic acid wasadded at RT. The reaction mixture was stirred at RT for 4 h and thendiluted with 10 ml of water. The phases were separated, and the aqueousphase was then extracted three more times with dichloromethane. Thecombined organic phases were dried over magnesium sulphate andconcentrated under reduced pressure. The crude product obtained in thismanner was purified by preparative RP HPLC (mobile phase methanol/water8:2 isocratic). This gave 56 mg of the target compound (81% of theory).

LC-MS (Method 5): R_(t)=1.20 min; m/z=488/490 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.02-0.10 (m, 1H), 0.19-0.33 (m, 2H),0.44-0.53 (m, 1H), 0.80 (d, 3H), 0.89-0.99 (m, 1H), 2.20-2.29 (m, 1H),2.47-2.68 (m, 2H, partially obscured by DMSO signal), 3.30-3.43 (m, 1H,partially obscured by H₂O signal), 4.13 (d, 1H), 7.10 (dd, 1H), 7.36 (d,1H), 7.42 (d, 1H), 7.43-7.50 (m, 4H), 9.84 (s, 1H), 12.04 (br. s, 1H).

[α]_(D) ²⁰=+98.8°, c=0.325, chloroform.

The compounds listed in the table below were prepared in an analogousmanner:

Example Name/Structure/Starting material Analytical data 23

LC-MS (Method 5): R_(t) = 1.20 min; m/z = 488/490 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.03-0.12 (m, 1H), 0.19-0.35 (m, 2H), 0.44-0.54(m, 1H), 0.80 (d, 3H), 0.88-0.99 (m, 1H), 2.20-2.29 (m, 1H), 2.47-2.69(m, 2H, partially obscured by DMSO signal), 3.29-3.43 (m, 1H, partiallyobscured by H₂O signal), 4.13 (d, 1H), 7.10 (dd, 1H), 7.36 (d, 1H), 7.41(d, 1H), 7.43-7.50 (m, 4H), 9.84 (s, 1H), 12.03 (br. s, 1H). [α]_(D) ²⁰= +57.3°, c = 0.355, chloroform. from tert-butyl3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoate (diastereomer 1) 24

LC-MS (Method 5): R_(t) = 1.31 min; m/z = 502 (M + H)⁺. ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.80 (d, 3H), 1.44-1.62 (m, 2H), 1.62-1.75 (m, 3H),1.97-2.02 (m, 1H), 2.29 (dd, 1H), 2.33-2.42 (m, 1H), 2.46 (dd, 1H), 2.87(td, 1H), 3.36-3.42 (m, 1H), 4.13 (d, 1H), 7.01 (dd, 1H), 7.33 (d, 1H),7.37 (t, 1H), 7.43-7.51 (m, 4H), 9.81 (s, 1H), 11.99 (br. s, ca. 1H).from tert-butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclobutylpropanoate (diastereomer mixture) 25

LC-MS (Method 7): R_(t) = 1.26 min; m/z = 520/522 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.80 (d, 3H), 0.94 (d, 3H), 1.00 (d, 3H),1.33-1.40 (m, 1H), 2.70-2.78 (m, 1H), 3.10 (s, 3H), 3.11-3.18 (m, 1H),3.32-3.44 (m, 1H, partially obscured by H₂O signal), 4.12 (d, 1H), 7.08(dd, 1H), 7.33 (dd, 1H), 7.42 (d, 1H), 7.43-7.50 (m, 4H), 9.83 (d, 1H),11.91 (br. s, ca. 1H). from tert-butyl3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-methoxy-4-methyl-pentanoate (diastereomer mixture) 26

LC-MS (Method 5): R_(t) = 1.27 min (diastereomer 1), m/z = 502/504 (M +H)⁺; R_(t) = 1.31 min (diastereomer 2), m/z = 502/504 (M + H)⁺. ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.80 (d, 3H), 0.88-0.96 (m, 5H), 1.66-1.78(m, 2H), 2.76-2.85 (m, 1H), 3.05-3.17 (m, 1H), 3.30-3.45 (m, 1H,partially obscured by H₂O signal), 3.57-3.66 (m, 1H), 4.10-4.18 (m, 1H),7.19 (dd, 1H), 7.40-7.51 (m, 6H), 9.92 (d, 1H). from tert-butyl3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-(1-methylcyclopropyl)-propanoate (diastereomer mixture) 27

LC-MS (Method 5): R_(t) = 1.18 min; m/z = 506/508 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.65-0.90 (m, 2H), 0.80 (d, 3H), 0.90-1.08 (m,1H), 1.11-1.31 (m, 1H), 1.56-1.73 (m, 1H), 2.69-2.89 (m, 2H), 3.30-3.44(m, 1H, partially obscured by H₂O signal), 4.13 (d, 1H), 7.14 (dd, 1H),7.39 (d, 1H), 7.42-7.52 (m, 5H), 9.87 (s, 1H), 11.85-12.70 (br. s, 1H).from tert-butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-(1-fluorocyclopropyl)-propanoate (diastereomer mixture) 28

LC-MS (Method 5): R_(t) = 1.24 min; m/z = 538/540 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.80 (d, 2.29H), 1.21-1.31 (m, 1.71H),2.02-2.17 (m, 1H), 2.18-2.39 (m, 3H), 2.40-2.75 (m, 2H, partiallyobscured by DMSO signal), 2.91-3.03 (m, 1H), 3.17-3.44 (m, 1H, partiallyobscured by H₂O signal), 4.13 (d, 1H), 7.05-7.16 (m, 1H), 7.33-7.53 (m,6H), 9.85 (s, 0.7H), 9.98 (s, 0.3H), 11.96- 12.18 (br. s, 1H). fromtert-butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-(3,3-difluorocyclobutyl)propanoate (diastereomer mixture) 29

LC-MS (Method 5): R_(t) = 1.29 min; m/z = 502/504 (M + H)⁺. fromtert-butyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chloro-phenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-cyclopropylbutanoate (diastereomer mixture)

Example 303-(4-Chloro-3-{[(3R)-2-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropyl-2-methylpropanoicacid (diastereomer mixture)

250 mg (0.47 mmol) of ethyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorphenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropyl-2-methylpropanoate(diastereomer mixture; Example 129A) were dissolved in a mixture of 1.0ml of methanol, 0.5 ml of THF and 0.5 ml of water, and 40 mg (0.94 mmol)of lithium hydroxide monohydrate were added at 0° C. The mixture wasstirred initially at 0° C. for 1 h and then at RT overnight. Another 40mg (0.94 mmol) of lithium hydroxide monohydrate were then added, and thereaction solution was warmed to 50° C. After further stirring at thistemperature overnight, 1 ml of methanol was metered into the reactionmixture, and the mixture was stirred at 60° C. for a further 12 h. Thesolution was then diluted with water and acidified with 1 N hydrochloricacid (pH about 2). The aqueous phase was extracted three times withethyl acetate. The combined organic phases were dried over magnesiumsulphate and concentrated under reduced pressure. This gave 204 mg (86%of theory) of the title compound as a diastereomer mixture.

LC-MS (Method 7): R_(t)=1.26 min, m/z=502/504 (M+H)⁺ (diastereomer 1);R_(t)=1.27 min, m/z=502/504 (M+H)⁺ (diastereomer 2); R_(t)=1.28 min,m/z=502/504 (M+H)⁺ (diastereomer 3); R_(t)=1.30 min, m/z=502/504 (M+H)⁺(diastereomer 4).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=−0.20-−0.05 (m, 0.85H), 0.13-0.36 (m,2H), 0.47-0.65 (m, 0.85H), 0.68-0.75 (m, 0.31H), 0.80 (d, 2.63H),0.93-1.09 (m, 1H), 1.17 (d, 1.5H), 1.21-1.29 (m, 1.87H), 1.84-2.08 (m,1H), 2.61-2.77 (m, 1H), 3.16-3.27 (m, 0.5H), 3.28-3.43 (m, 0.5H,partially obscured by H₂O signal), 4.09-4.17 (m, 1H), 6.70-6.78 (m,0.16H), 7.02-7.13 (m, 1H), 7.30-7.53 (m, 5.84H), 9.80-10.01 (m, 1H),11.79-12.35 (br. m, 1H).

Example 313-(4-Chloro-3-{[(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-(2,2-difluorocyclopropyl)propanoicacid (diastereomer mixture 1)

114 mg (0.21 mmol) of methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorphenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-(2,2-difluorocyclopropyl)propanoate(isomer 1; Example 124A) were dissolved in a mixture of 2 ml of dioxaneand 1 ml of water, and 27 mg (0.64 mmol) of lithium hydroxidemonohydrate were added. The mixture was stirred at RT overnight. Thesolution was then diluted with water and acidified with 1 N hydrochloricacid (pH about 2). The precipitated solid was filtered off with suctionand dried under high vacuum overnight. This gave 89 mg (80% of theory)of the title compound as a diastereomer mixture in the form of a whitesolid.

LC-MS (Method 5): R_(t)=1.26 min; m/z=524/526 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.80 (d, 1.63H), 1.04-1.19 (m, 1H),1.26 (d, 1.37H), 1.36-1.50 (m, 1H), 1.97-2.14 (m, 1H), 2.46-2.82 (m, 3H,partially obscured by DMSO signal), 3.15-3.43 (m, 1H, partially obscuredby H₂O signal), 4.07-4.17 (m, 1H), 7.17-7.26 (m, 1H), 7.36-7.53 (m, 6H),9.87 (s, 0.55H), 10.01 (s, 0.45H), 12.16 (br. s, 1H).

Example 323-(4-Chloro-3-{[(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-(2,2-difluorocyclopropyl)propanoicacid (diastereomer mixture 2)

115 mg (0.21 mmol) of methyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorphenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-(2,2-difluorocyclopropyl)propanoate(isomer 2; Example 125A) were dissolved in a mixture of 2 ml of dioxaneand 1 ml of water, and 27 mg (0.64 mmol) of lithium hydroxidemonohydrate were added. The mixture was stirred at RT overnight. Thesolution was then diluted with water and acidified with 1 N hydrochloricacid (pH about 2). The aqueous phase was extracted three times withdichloromethane. The combined organic phases were dried over magnesiumsulphate and concentrated under reduced pressure. This gave 101 mg (90%of theory) of the title compound as a diastereomer mixture in the formof a colourless oil.

LC-MS (Method 5): R_(t)=1.26 min; m/z=524/526 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.80 (d, 1.68H), 1.05-1.18 (m, 1H),1.26 (d, 1.32H), 1.35-1.50 (m, 1H), 1.96-2.12 (m, 1H), 2.44-2.82 (m, 3H,partially obscured by DMSO signal), 3.15-3.42 (m, 1H, partially obscuredby H₂O signal), 4.08-4.16 (m, 1H), 7.17-7.25 (m, 1H) 7.37-7.52 (m, 6H),9.87 (s, 0.56H), 10.01 (s, 0.44H), 12.16 (br. s, 1H).

Example 33 and Example 34(+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclobutylpropanoicacid (diastereomer 1 and 2)

The diastereomer mixture obtained above of3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclobutylpropanoicacid (Example 24) was separated further by preparative HPLC on a chiralphase [column: Daicel Chiralpak AD-H, S pun, 250 mm×20 mm; injectionvolume: 0.40 ml; mobile phase: 90% isohexane/10% isopropanol; flow rate:15 ml/min; detection: 220 nm; temperature: 25° C.]. 63 mg ofdiastereomer mixture gave 29 mg of diastereomer 1 (Example 33) and 32 mgof diastereomer 2 (Example 34).

Example 33 Diastereomer 1

LC-MS (Method 5): R_(t)=1.31 min; m/z=502 (M+H).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.80 (d, 3H), 1.45-1.62 (m, 2H),1.62-1.79 (m, 3H), 1.97-2.03 (m, 1H), 2.24-2.39 (m, 2H), 2.42-2.47 (m,1H), 2.87 (d, 1H), 3.35-3.40 (m, 1H), 4.13 (d, 1H), 7.01 (dd, 1H),7.23-7.39 (m, 2H), 7.42-7.54 (m, 4H), 9.81 (s, 1H), 11.98 (br. s, 1H).

[α]_(D) ²⁰=+69°, c=0.260, chloroform.

Example 34 (Diastereomer 2)

LC-MS (Method 5): R_(t)=1.31 min; m/z=502 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₄): δ [ppm]=0.80 (d, 3H), 1.45-1.63 (m, 2H),1.63-1.76 (m, 3H), 1.98-2.04 (m, 1H), 2.22-2.42 (m, 2H), 2.44-2.48 (m,1H), 2.87 (td, 1H), 4.13 (d, 1H), 7.02 (dd, 1H), 7.33 (d, 11H), 7.37 (d,1H), 7.42-7.51 (m, 4H), 9.81 (s, 1H), 12.00 (br. s, 1H).

[α]_(D) ²⁰=+53°, c=0.250, chloroform.

Example 35 and Example 363-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-cyclopropylbutanoicacid (diastereomer 1 and 2)

55 mg (0.11 mmol) of the diastereomer mixture of3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-cyclopropylbutanoicacid (Example 29) were separated further by preparative HPLC on a chiralphase [column: Daicel Chiralpak AD-H, 5 μm, 250 mm×20 mm; mobile phase:isohexane/ethanol 90:10 (v/v); flow rate: 15 ml/min; UV detection: 220nm; temperature: 30° C.]:

Example 35 (Diastereomer 1)

Yield: 28 mg

R_(t)=7.47 min; chemical purity >99%; >99% de

[Column: Chiralpak AD-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/(ethanol+0.2% trifluoroacetic acid+1% water) 90:10 (v/v); flowrate: 1 ml/min; UV detection: 220 nm; temperature: 30° C.].

LC-MS (Method 5): R_(t)=1.26 min; m/z=502/504 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=−0.14-−0.06 (m, 1H), −0.06-−0.03 (m,1H) 0.22-0.37 (m, 2H), 0.39-0.50 (m, 11H), 0.80 (d, 3H), 1.27-1.36 (m,11H), 1.45-1.56 (m, 1H), 2.39-2.47 (m, 1H), 2.57-2.66 (m, 1H), 2.99-3.09(m, 1H), 3.28-3.43 (m, 1H, partially obscured by H₂O signal), 4.13 (d,1H), 7.07 (dd, 1H), 7.35 (d, 1H), 7.41 (d, 1H), 7.43-7.50 (m, 1H), 9.82(s, 1H), 12.02 (br. s, 1H).

[α]_(D) ²⁰=+41°, c=0.260, chloroform.

Example 36 (Diastereomer 2)

Yield: 25 mg

R_(t)=8.75 min; chemical purity >99%; >98.7% de

[Column: Chiralpak AD-H, 5 μm, 250 mm×4.6 mm; mobile phase:isohexane/(ethanol+0.2% trifluoroacetic acid+1% water) 90:10 (v/v); flowrate: 1 ml/min; UV detection: 220 nm; temperature: 30° C.].

LC-MS (Method 5): R_(t)=1.26 min; m/z=502/504 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=−0.14-−0.07 (m, 1H), −0.06-−0.02 (m,1H), 0.22-0.36 (m, 2H), 0.38-0.49 (m, 1H), 0.80 (d, 3H), 1.27-1.36 (m,1H), 1.46-1.55 (m, 1H), 2.39-2.47 (m, 1H), 2.58-2.66 (m, 1H), 2.99-3.09(m, 1H), 3.28-3.43 (m, 1H, partially obscured by H₂O signal), 4.13 (d,1H), 7.07 (dd, 1H), 7.35 (d, 1H), 7.42 (d, 1H), 7.43-7.50 (m, 4H), 9.82(s, 1H), 12.02 (br. s, 1H).

The following compound was prepared analogously to Example 22:

Example Name/Structure/Starting material Analytical data 37

LC-MS (Method 7): R_(t) = 1.34 min; m/z = 516/518 (M + H)⁺. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = −0.16-−0.09 (m, 1H), −0.09- −0.02 (m, 1H),0.11-0.18 (m, 1H), 0.18-0.25 (m, 1H), 0.80 (d, 3H), 0.92 (d, 3H),1.47-1.55 (m, 2H), 2.31-2.42 (m, 1H), 2.57-2.65 (m, 1H), 3.05-3.20 (m,1H), 3.28- 3.43 (m, 1H, partially obscured by H₂O signal), 4.12 (d, 1H),7.01- 7.13 (m, 1H), 7.33 (d, 1H), 7.39- 7.51 (m, 5H), 9.81 (d, 1H),12.03 (br. s, 1H). from tert-butyl3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-4-(1-methylcyclopropyl)-butanoate (diastereomer mixture)

B. ASSESSMENT OF THE PHARMACOLOGICAL ACTIVITY

The pharmacological effect of the compounds according to the inventioncan be shown in the following assays:

B-1. Stimulation of Recombinant Soluble Granulate Cyclase (sGC) In Vitro

Investigations on the stimulation of recombinant soluble guanylatecyclase (sGC) by the compounds according to the invention with andwithout sodium nitroprusside, and with and without the haem-dependentsGC inhibitor 1H-1,2,4-oxadiazolo[4,3a]quinoxalin-1-one (ODQ), arecarried out by the method described in detail in the followingreference: M. Hoenicka, E. M. Becker, H. Apeler, T. Sirichoke. H.Schroeder, R. Gerzer and J.-P. Stasch, “Purified soluble guanylylcyclase expressed in a baculovirus/Sf9 system: Stimulation by YC-1,nitric oxide, and carbon oxide”, J. Mol. Med. 77 (1999), 14-23. Thehaem-free guanylate cyclase is obtained by adding Tween 20 to the samplebuffer (0.5% in the final concentration).

The activation of sGC by a test substance is reported as x-foldstimulation of the basal activity. The result for Example 22 is shown inTable 1:

TABLE 1 Stimulation (x-fold) of recombinant soluble guanylate cyclase(sGC) in vitro by Example 22 Concentration Haem-free ExampleHaem-containing sGC sGC 22 Basal +0.01 μM +10 μM Basal [μM] (n = 5)DEA/NO ODQ (n = 5) 0 1.0 ± 0.0 3.6 ± 1.0  5.1 ± 1.5  1.0 ± 0.0 0.01 1.6± 0.3 4.4 ± 1.3  5.7 ± 1.6  1.2 ± 0.1 0.1 1.6 ± 0.5 3.4 ± 0.9  6.1 ± 1.7 1.6 ± 0.5 1.0 2.4 ± 1.0 4.4 ± 1.4  8.4 ± 2.2  4.9 ± 1.5 10 4.9 ± 1.27.8 ± 2.5 18.3 ± 5.4 14.2 ± 2.0 [DEA/NO =2-(N,N-diethylamino)diazenolate 2-oxide; ODQ =1H-1,2,4-oxadiazolo-[4,3a]quinoxalin-1-one].

It is evident from Table 1 that stimulation both of the haem-containingand of the haem-free enzyme is achieved. Furthermore, combination ofExample 22 and 2-(N,N-diethylamino)-diazenolate 2-oxide (DEA/NO), an NOdonor, shows no synergistic effect, i.e. the effect of DEA/NO is notpotentiated as would be expected with an sGC activator acting via ahaem-dependent mechanism. In addition, the effect of the sGC activatoraccording to the invention is not blocked by1H-1,2,4-oxadiazolo[4,3a]quinoxalin-1-one (ODQ), a haem-dependentinhibitor of soluble guanylate cyclase, but is in fact increased. Theresults in Table 1 thus confirm the mechanism of action of the compoundsaccording to the invention as activators of soluble guanylate cyclase.

B-2. Action at a Recombinant Granulate Cyclase Reporter Cell Line

The cellular action of the compounds according to the invention isdetermined at a recombinant guanylate cyclase reporter cell line, asdescribed in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).

Representative results for the compounds according to the invention arelisted in Table 2:

TABLE 2 sGC-activating activity in the CHO reporter cell in vitroExample No. MEC [nM] 1 3 2 6.5 3 0.3 4 3 5 0.3 6 1 7 300 8 1 9 1 10 0.311 3 12 1 13 0.3 14 0.3 15 3 16 3 17 1 18 300 19 30 20 1000 21 10 22 1.823 3 25 10 26 10 27 3 28 30 30 10 31 3 32 3 33 1 34 10 35 0.3 36 3 (MEC= minimum effective concentration).B-3. Stimulation of sGC Enzyme Activity

Soluble guanylate cyclase (sGC) converts on stimulation GTP into cGMPand pyrophosphate (PPi). PPi is detected with the aid of the assaydescribed below. The signal produced in the assay increases as thereaction progresses and serves as a measure of the sGC enzyme activityunder the given stimulation.

To carry out the assay, 29 μl of enzyme solution [0-10 nM solubleguanylate cyclase (prepared according to Hönicka et al, J. Mol. Med. 77,14-23 (1999)) in 50 mM TEA, 2 mM MgC₂, 0.1% BSA (fraction V), 0.005%Brij®, pH 7.5] are initially introduced into a microplate, and 1 μl ofthe substance to be tested (as a serially diluted solution in DMSO) isadded. The mixture is incubated at room temperature for 10 min. Then 20μl of detection mix [1.2 nM Firefly Luciferase (Photinus pyralisluciferase, Promega), 29 μM dehydroluciferin (prepared according toBitler & McElroy, Arch. Biochem. Biophys. 72, 358 (1957)), 122 μMluciferin (Promega), 153 μM ATP (Sigma) and 0.4 mM DTT (Sigma) in 50 mMTEA, 2 mM MgCl₂, 0.1% BSA (fraction V), 0.005% Brij®, pH 7.5] are added.The enzyme reaction is started by adding 20 μl of substrate solution[1.25 mM guanosine 5′-triphosphate (Sigma) in 50 mM TEA, 2 mM MgC₂, 0.1%BSA (fraction V), 0.005% Brij®, pH 7.5] and measured continuously in aluminometer. The extent of the stimulation by the substance to be testedcan be determined relative to the signal of the unstimulated reaction.

The activation of haem-free guanylate cyclase is examined by addition of25 μM of 1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) to the enzymesolution and subsequent incubation for 30 minutes and compared to thestimulation of the native enzyme.

Representative results for the compounds according to the invention arelisted in Table 3:

TABLE 3 Activating action at the sGC enzyme in vitro Example No. MEC[nM] EC₅₀ [nM] 1 1 22 2 4 89 3 1 37 4 2.4 110 5 0.3 5.2 6 1.1 56 10 0.510 12 1.1 17 13 0.5 14 14 0.5 8.4 22 2.4 68 25 5.1 220 27 1.7 68 30 1.7640 33 0.4 11 35 1 11 (MEC = minimum effective concentration; EC₅₀ =concentration at 50% of maximum efficacy).B-4. Vasorelaxant Effect In Vitro

Rabbits are anaesthetized and sacrificed by intravenous injection ofthiopental sodium (about 50 mg/kg) and exsanguinated. The saphenousartery is removed and divided into rings 3 mm wide. The rings aremounted singly on in each case a pair of triangular hooks open at theend and made of 0.3 mm-thick special wire (Remanium®). Each ring isplaced under an initial tension in 5 ml organ baths with Krebs-Henseleitsolution which is at 37° C., is gassed with carbogen and has thefollowing composition: NaCl 119 mM; KCl 4.8 mM; CaCl₂×2 H₂O 1 mM;MgSO₄×7 H₂O 1.4 mM; KH₂PO₄ 1.2 mM; NaHCO₃ 25 mM; glucose 10 mM; bovineserum albumin 0.001%. The force of contraction is detected with StathamUC2 cells, amplified and digitized via A/D converters (DAS-1802 HC,Keithley Instruments, Munich) and recorded in parallel on chartrecorders. Contractions are induced by addition of phenylephrine.

After several (generally 4) control cycles, the substance to beinvestigated is added in each further run in increasing dosage, and thelevel of the contraction achieved under the influence of the testsubstance is compared with the level of the contraction reached in thelast preceding run. The concentration necessary to reduce thecontraction reached in the preceding control by 50% is calculated fromthis (IC₅₀). The standard application volume is 5 μl. The proportion ofDMSO in the bath solution corresponds to 0.1%.

Representative results for the compounds according to the invention arelisted in Table 4:

TABLE 4 Vasorelaxant effect in vitro Example No. IC₅₀ [nM] 3 801 10 13114 269 16 767 22 137B-5. Radiotelemetric Measurement of Blood Pressure and Heart Rate onConscious SH Rats

A commercially available telemetry system from Data SciencesInternational DSI, USA, is employed for the measurements on conscious SHrats described below.

The system consists of 3 main components: (1) implantable transmitters,(2) receivers, which are linked via a multiplexer to a (3) dataacquisition computer. The telemetry system makes it possible tocontinuously record the blood pressure and heart rate of consciousanimals in their usual habitat.

The investigations are carried out on adult female spontaneouslyhypertensive rats (SH rats) with a body weight of >200 g. Aftertransmitter implantation, the experimental animals are housed singly intype 3 Makrolon cages. They have free access to standard feed and water.The day/night rhythm in the experimental laboratory is changed by theroom lighting at 6.00 am and at 7.00 pm.

The telemetry transmitters (TAM PA-C40, DSI) employed are surgicallyimplanted under aseptic conditions in the experimental animals at least14 days before the first experimental use. The animals instrumented inthis way can be employed repeatedly after the wound has healed and theimplant has settled.

For the implantation, the fasted animals are anaesthetized withpentobarbital (Nembutal, Sanofi, 50 mg/kg i.p.) and shaved anddisinfected over a large area of their abdomens. After the abdominalcavity has been opened along the linea alba, the liquid-filled measuringcatheter of the system is inserted into the descending aorta in thecranial direction above the bifurcation and fixed with tissue glue(VetBonD™, 3M). The transmitter housing is fixed intraperitoneally tothe abdominal wall muscle, and layered closure of the wound isperformed. An antibiotic (Tardomyocel COMP, Bayer AG, 1 ml/kg s.c.) isadministered postoperatively for prophylaxis of infection.

Outline of Experiment:

The substances to be investigated are administered orally by gavage ineach case to a group of animals (n=6). The test substances are dissolvedin suitable solvent mixtures, or suspended in 0.5% strength Tylose,appropriate for an administration volume of 5 ml/kg of body weight. Asolvent-treated group of animals is employed as control.

The telemetry measuring unit is configured for 24 animals. Eachexperiment is recorded under an experiment number.

Each of the instrumented rats living in the system is assigned aseparate receiving antenna (1010 Receiver, DSI). The implantedtransmitters can be activated externally by means of an incorporatedmagnetic switch and are switched to transmission in the run-up to theexperiment. The emitted signals can be detected online by a dataacquisition system (Dataquest™ A.R.T. for Windows, DSI) and beappropriately processed. The data are stored in each case in a filecreated for this purpose and bearing the experiment number.

In the standard procedure, the following are measured for 10-secondperiods in each case: (1) systolic blood pressure (SBP), (2) diastolicblood pressure (DBP), (3) mean arterial pressure (MAP) and (4) heartrate (HR).

The acquisition of measured values is repeated under computer control at5-minute intervals. The source data obtained as absolute value arecorrected in the diagram with the currently measured barometric pressureand stored as individual data. Further technical details are given inthe documentation from the manufacturing company (DSI).

The test substances are administered at 9.00 am on the day of theexperiment. Following the administration, the parameters described aboveare measured over 24 hours. After the end of the experiment, theacquired individual data are sorted using the analysis software(Dataquest™ A.R.T. Analysis). The void value is assumed to be the time 2hours before administration of the substance, so that the selected dataset includes the period from 7.00 am on the day of the experiment to9.00 am on the following day.

The data are smoothed over a presettable time by determination of theaverage (15-minute average, 30-minute average) and transferred as a textfile to a storage medium. The measured values presorted and compressedin this way are transferred into Excel templates and tabulated.

C. EXEMPLARY EMBODIMENTS OF PHARMACEUTICAL COMPOSITIONS

The compounds according to the invention can be converted intopharmaceutical preparations in the following ways:

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg of lactose(monohydrate), 50 mg of maize starch (native), 10 mg ofpolyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2mg of magnesium stearate.

Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of compound according to the invention, lactose and starchis granulated with a 5% strength solution (m/m) of the PVP in water. Thegranules are dried and then mixed with the magnesium stearate for 5minutes. This mixture is compressed in a conventional tablet press (seeabove for format of the tablet). A guideline compressive force for thecompression is 15 kN.

Suspension which can be Administered Orally:

Composition:

1000 mg of the compound according to the invention, 1000 mg of ethanol(96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and99 g of water.

10 ml of oral suspension correspond to a single dose of 100 mg of thecompound according to the invention.

Production:

The Rhodigel is suspended in ethanol, and the compound according to theinvention is added to the suspension. The water is added while stirring.The mixture is stirred for about 6 h until the swelling of the Rhodigelis complete.

Solution which can be Administered Orally:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbateand 97 g of polyethylene glycol 400. 20 g of oral solution correspond toa single dose of 100 mg of the compound according to the invention.

Production:

The compound according to the invention is suspended in the mixture ofpolyethylene glycol and polysorbate with stirring. The stirring processis continued until the compound according to the invention hascompletely dissolved.

i.v. Solution:

The compound according to the invention is dissolved in a concentrationbelow the saturation solubility in a physiologically tolerated solvent(e.g. isotonic saline, 5% glucose solution and/or 30% PEG 400 solution).The solution is sterilized by filtration and used to fill sterile andpyrogen-free injection containers.

The invention claimed is:
 1. A process for preparing (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of formula:

or a salt, solvate, or solvate of a salt thereof, comprising coupling a carboxylic acid of formula (II)

in which R^(8A) represents methyl, R^(8B) represents trifluoromethyl, R⁹ represents chlorine and R¹⁰ represents hydrogen, in an inert solvent with the aid of a condensing agent or via the intermediate of the corresponding carbonyl chloride in the presence of a base with an amine of formula (III)

in which L represents a bond, R¹, R², R³, R⁵, and R⁷ independently of one another represent hydrogen, R^(4A) and R^(4B) are attached to one another and together with the carbon atom to which they are attached form a cyclopropyl ring, R⁶ represents chlorine, and T¹ represents (C₁-C₄)-alkyl or benzyl, to give a carboxamide of the formula (IV)

and removing T¹ from the compound of formula (IV) by basic or acidic solvolysis or, when T¹ represents benzyl, also by hydrogenolysis.
 2. The process of claim 1, wherein the removing of T¹ from the compound of formula (IV) results in formation of (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of formula:


3. A method for the treatment and/or prevention of heart failure, renal insufficiency, diabetic retinopathy, and vascular dementia comprising administering an effective amount of (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of formula:

or a salt, solvate, or solvate of a salt thereof to a human or animal in need thereof.
 4. The method for treatment and/or prevention according to claim 3, further comprising administering a second active compound selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, stimulators of guanylate cyclase, agents having antithrombotic activity, agents for lowering blood pressure, and agents for altering lipid metabolisms.
 5. A method for the treatment and/or prevention of renal insufficiency comprising administering an effective amount of (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of formula:

or a salt, solvate, or solvate of a salt thereof to a human or animal in need thereof.
 6. The method of claim 5, wherein a therapeutically effective amount of (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of formula:

is administered.
 7. A method for the treatment and/or prevention of renal insufficiency comprising administering an effective amount of a pharmaceutical composition comprising (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of formula:

or a salt, solvate, or solvate of a salt thereof and an inert, non-toxic, pharmaceutically suitable excipient to a human or animal in need thereof.
 8. The method of claim 7, wherein the pharmaceutical composition comprises (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of formula: 